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Entry
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- *604167 - CCCTC-BINDING FACTOR; CTCF
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- OMIM
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<div id="mimFloatingTocMenu" class="small" role="navigation">
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<p>
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<span class="h4">*604167</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<li role="presentation">
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<a href="#title"><strong>Title</strong></a>
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<a href="#geneMap"><strong>Gene-Phenotype Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#description">Description</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#cloning">Cloning and Expression</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#mapping">Mapping</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#biochemicalFeatures">Biochemical Features</a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#geneFunction">Gene Function</a>
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<a href="#molecularGenetics">Molecular Genetics</a>
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<li role="presentation">
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<a href="#allelicVariants"><strong>Allelic Variants</strong></a>
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</li>
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<li role="presentation" style="margin-left: 1em">
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<a href="/allelicVariants/604167">Table View</a>
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<li role="presentation">
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<a href="#references"><strong>References</strong></a>
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</li>
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<li role="presentation">
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<a href="#contributors"><strong>Contributors</strong></a>
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<li role="presentation">
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<a href="#creationDate"><strong>Creation Date</strong></a>
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</li>
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<li role="presentation">
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<a href="#editHistory"><strong>Edit History</strong></a>
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</li>
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</ul>
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<div class="col-lg-2 col-lg-push-8 col-md-2 col-md-push-8 col-sm-2 col-sm-push-8 col-xs-12">
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<h4 class="panel-title">
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<a href="#mimExternalLinksFold" id="mimExternalLinksToggle" class="mimTriangleToggle" role="button" data-toggle="collapse">
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<div style="display: table-row">
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<div id="mimExternalLinksToggleTriangle" class="small" style="color: white; display: table-cell;">▼</div>
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<div style="display: table-cell;">External Links</div>
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</div>
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</a>
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</h4>
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</div>
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</div>
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<div id="mimExternalLinksFold" class="collapse in">
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<div class="panel-group" id="mimExternalLinksAccordion" role="tablist" aria-multiselectable="true">
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGenome">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGenomeLinksFold" id="mimGenomeLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimGenomeLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Genome
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</a>
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</span>
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</span>
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</div>
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<div id="mimGenomeLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="genome">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Location/View?db=core;g=ENSG00000102974;t=ENST00000264010" class="mim-tip-hint" title="Genome databases for vertebrates and other eukaryotic species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/genome/gdv/browser/gene/?id=10664" class="mim-tip-hint" title="Detailed views of the complete genomes of selected organisms from vertebrates to protozoa." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Genome Viewer', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Genome Viewer</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=604167" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimDna">
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<span class="panel-title">
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<span class="small">
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<a href="#mimDnaLinksFold" id="mimDnaLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimDnaLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> DNA
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</a>
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</span>
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<div id="mimDnaLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ensembl.org/Homo_sapiens/Transcript/Sequence_cDNA?db=core;g=ENSG00000102974;t=ENST00000264010" class="mim-tip-hint" title="Transcript-based views for coding and noncoding DNA." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl (MANE Select)</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_001191022,NM_001363916,NM_006565,XM_005255775,XM_017022868" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_006565" class="mim-tip-hint" title="A collection of genome, gene, and transcript sequence data from several sources, including GenBank, RefSeq." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI RefSeq (MANE)', 'domain': 'ncbi.nlm.nih'})">NCBI RefSeq (MANE Select)</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&hgFind=omimGeneAcc&position=604167" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">UCSC Genome Browser</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimProtein">
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<span class="panel-title">
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<span class="small">
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<a href="#mimProteinLinksFold" id="mimProteinLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimProteinLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">►</span> Protein
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</a>
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</span>
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</span>
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</div>
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<div id="mimProteinLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://hprd.org/summary?hprd_id=05005&isoform_id=05005_1&isoform_name=Isoform_1" class="mim-tip-hint" title="The Human Protein Reference Database; manually extracted and visually depicted information on human proteins." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HPRD', 'domain': 'hprd.org'})">HPRD</a></div>
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<div><a href="https://www.proteinatlas.org/search/CTCF" class="mim-tip-hint" title="The Human Protein Atlas contains information for a large majority of all human protein-coding genes regarding the expression and localization of the corresponding proteins based on both RNA and protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HumanProteinAtlas', 'domain': 'proteinatlas.org'})">Human Protein Atlas</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/protein/924760,1706179,5729790,6910966,15679930,32880173,50834322,62089172,119603548,119603549,119603550,119603551,119603552,193787500,300388142,530423538,1034593398,1394533437,2462547114,2462547116" class="mim-tip-hint" title="NCBI protein data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Protein', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Protein</a></div>
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<div><a href="https://www.uniprot.org/uniprotkb/P49711" class="mim-tip-hint" title="Comprehensive protein sequence and functional information, including supporting data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UniProt', 'domain': 'uniprot.org'})">UniProt</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimGeneInfo">
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<span class="panel-title">
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<span class="small">
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<a href="#mimGeneInfoLinksFold" id="mimGeneInfoLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimGeneInfoLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Gene Info</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimGeneInfoLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="http://biogps.org/#goto=genereport&id=10664" class="mim-tip-hint" title="The Gene Portal Hub; customizable portal of gene and protein function information." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'BioGPS', 'domain': 'biogps.org'})">BioGPS</a></div>
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<div><a href="https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000102974;t=ENST00000264010" class="mim-tip-hint" title="Orthologs, paralogs, regulatory regions, and splice variants." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Ensembl', 'domain': 'ensembl.org'})">Ensembl</a></div>
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<div><a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=CTCF" class="mim-tip-hint" title="The Human Genome Compendium; web-based cards integrating automatically mined information on human genes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneCards', 'domain': 'genecards.org'})">GeneCards</a></div>
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<div><a href="http://amigo.geneontology.org/amigo/search/annotation?q=CTCF" class="mim-tip-hint" title="Terms, defined using controlled vocabulary, representing gene product properties (biologic process, cellular component, molecular function) across species." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GeneOntology', 'domain': 'amigo.geneontology.org'})">Gene Ontology</a></div>
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<div><a href="https://www.genome.jp/dbget-bin/www_bget?hsa+10664" class="mim-tip-hint" title="Kyoto Encyclopedia of Genes and Genomes; diagrams of signaling pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'KEGG', 'domain': 'genome.jp'})">KEGG</a></div>
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<dd><a href="http://v1.marrvel.org/search/gene/CTCF" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></dd>
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<dd><a href="https://monarchinitiative.org/NCBIGene:10664" class="mim-tip-hint" title="Monarch Initiative." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Monarch', 'domain': 'monarchinitiative.org'})">Monarch</a></dd>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/10664" class="mim-tip-hint" title="Gene-specific map, sequence, expression, structure, function, citation, and homology data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Gene', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Gene</a></div>
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<div><a href="https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_chrom=chr16&hgg_gene=ENST00000264010.10&hgg_start=67562526&hgg_end=67639185&hgg_type=knownGene" class="mim-tip-hint" title="UCSC Genome Bioinformatics; gene-specific structure and function information with links to other databases." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC', 'domain': 'genome.ucsc.edu'})">UCSC</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimClinicalResources">
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<span class="panel-title">
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<span class="small">
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<a href="#mimClinicalResourcesLinksFold" id="mimClinicalResourcesLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimClinicalResourcesLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Clinical Resources</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimClinicalResourcesLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel" aria-labelledby="clinicalResources">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://search.clinicalgenome.org/kb/gene-dosage/HGNC:13723" class="mim-tip-hint" title="A ClinGen curated resource of genes and regions of the genome that are dosage sensitive and should be targeted on a cytogenomic array." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Dosage', 'domain': 'dosage.clinicalgenome.org'})">ClinGen Dosage</a></div>
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<div><a href="https://search.clinicalgenome.org/kb/genes/HGNC:13723" class="mim-tip-hint" title="A ClinGen curated resource of ratings for the strength of evidence supporting or refuting the clinical validity of the claim(s) that variation in a particular gene causes disease." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinGen Validity', 'domain': 'search.clinicalgenome.org'})">ClinGen Validity</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=604167[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimVariation">
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<span class="panel-title">
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<span class="small">
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<a href="#mimVariationLinksFold" id="mimVariationLinksToggle" class=" mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<span id="mimVariationLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5">▼</span> Variation
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</a>
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</span>
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</span>
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</div>
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<div id="mimVariationLinksFold" class="panel-collapse collapse in mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.ncbi.nlm.nih.gov/clinvar?term=604167[MIM]" class="mim-tip-hint" title="ClinVar aggregates information about sequence variation and its relationship to human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">ClinVar</a></div>
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<div><a href="https://www.deciphergenomics.org/gene/CTCF/overview/clinical-info" class="mim-tip-hint" title="DECIPHER" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'DECIPHER', 'domain': 'DECIPHER'})">DECIPHER</a></div>
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<div><a href="https://gnomad.broadinstitute.org/gene/ENSG00000102974" class="mim-tip-hint" title="The Genome Aggregation Database (gnomAD), Broad Institute." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'gnomAD', 'domain': 'gnomad.broadinstitute.org'})">gnomAD</a></div>
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<div><a href="https://www.ebi.ac.uk/gwas/search?query=CTCF" class="mim-tip-hint" title="GWAS Catalog; NHGRI-EBI Catalog of published genome-wide association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Catalog', 'domain': 'gwascatalog.org'})">GWAS Catalog </a></div>
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<div><a href="https://www.gwascentral.org/search?q=CTCF" class="mim-tip-hint" title="GWAS Central; summary level genotype-to-phenotype information from genetic association studies." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GWAS Central', 'domain': 'gwascentral.org'})">GWAS Central </a></div>
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<div><a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=CTCF" class="mim-tip-hint" title="Human Gene Mutation Database; published mutations causing or associated with human inherited disease; disease-associated/functional polymorphisms." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGMD', 'domain': 'hgmd.cf.ac.uk'})">HGMD</a></div>
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<div><a href="https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=CTCF&upstreamSize=0&downstreamSize=0&x=0&y=0" class="mim-tip-hint" title="National Heart, Lung, and Blood Institute Exome Variant Server." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NHLBI EVS', 'domain': 'evs.gs.washington.edu'})">NHLBI EVS</a></div>
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<div><a href="https://www.pharmgkb.org/gene/PA26998" class="mim-tip-hint" title="Pharmacogenomics Knowledge Base; curated and annotated information regarding the effects of human genetic variations on drug response." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PharmGKB', 'domain': 'pharmgkb.org'})">PharmGKB</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimAnimalModels">
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<span class="panel-title">
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<span class="small">
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<a href="#mimAnimalModelsLinksFold" id="mimAnimalModelsLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimAnimalModelsLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Animal Models</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimAnimalModelsLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://www.alliancegenome.org/gene/HGNC:13723" class="mim-tip-hint" title="Search Across Species; explore model organism and human comparative genomics." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Alliance Genome', 'domain': 'alliancegenome.org'})">Alliance Genome</a></div>
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<div><a href="https://flybase.org/reports/FBgn0035769.html" class="mim-tip-hint" title="A Database of Drosophila Genes and Genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'FlyBase', 'domain': 'flybase.org'})">FlyBase</a></div>
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<div><a href="https://www.mousephenotype.org/data/genes/MGI:109447" class="mim-tip-hint" title="International Mouse Phenotyping Consortium." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'IMPC', 'domain': 'knockoutmouse.org'})">IMPC</a></div>
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<div><a href="http://v1.marrvel.org/search/gene/CTCF#HomologGenesPanel" class="mim-tip-hint" title="Model organism Aggregated Resources for Rare Variant ExpLoration." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MARRVEL', 'domain': 'marrvel.org'})">MARRVEL</a></div>
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<div><a href="http://www.informatics.jax.org/marker/MGI:109447" class="mim-tip-hint" title="Mouse Genome Informatics; international database resource for the laboratory mouse, including integrated genetic, genomic, and biological data." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MGI Mouse Gene', 'domain': 'informatics.jax.org'})">MGI Mouse Gene</a></div>
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<div><a href="https://www.mmrrc.org/catalog/StrainCatalogSearchForm.php?search_query=" class="mim-tip-hint" title="Mutant Mouse Resource & Research Centers." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MMRRC', 'domain': 'mmrrc.org'})">MMRRC</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gene/10664/ortholog/" class="mim-tip-hint" title="Orthologous genes at NCBI." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'NCBI Orthologs', 'domain': 'ncbi.nlm.nih.gov'})">NCBI Orthologs</a></div>
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<div><a href="https://www.orthodb.org/?ncbi=10664" class="mim-tip-hint" title="Hierarchical catalogue of orthologs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrthoDB', 'domain': 'orthodb.org'})">OrthoDB</a></div>
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<div><a href="https://zfin.org/ZDB-GENE-040624-5" class="mim-tip-hint" title="The Zebrafish Model Organism Database." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'ZFin', 'domain': 'zfin.org'})">ZFin</a></div>
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</div>
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</div>
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</div>
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<div class="panel panel-default" style="margin-top: 0px; border-radius: 0px">
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<div class="panel-heading mim-panel-heading" role="tab" id="mimCellularPathways">
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<span class="panel-title">
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<span class="small">
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<a href="#mimCellularPathwaysLinksFold" id="mimCellularPathwaysLinksToggle" class="collapsed mimSingletonTriangleToggle" role="button" data-toggle="collapse" data-parent="#mimExternalLinksAccordion">
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<div style="display: table-row">
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<div id="mimCellularPathwaysLinksToggleTriangle" class="small mimSingletonTriangle" style="color: #337CB5; display: table-cell;">►</div>
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<div style="display: table-cell;">Cellular Pathways</div>
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</div>
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</a>
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</span>
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</span>
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</div>
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<div id="mimCellularPathwaysLinksFold" class="panel-collapse collapse mimLinksFold" role="tabpanel">
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<div class="panel-body small mim-panel-body">
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<div><a href="https://reactome.org/content/query?q=CTCF&species=Homo+sapiens&types=Reaction&types=Pathway&cluster=true" class="definition" title="Protein-specific information in the context of relevant cellular pathways." target="_blank" onclick="gtag('event', 'mim_outbound', {{'name': 'Reactome', 'domain': 'reactome.org'}})">Reactome</a></div>
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</div>
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</div>
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</div>
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</div>
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</div>
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</div>
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<span>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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</span>
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</span>
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</div>
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<div class="col-lg-8 col-lg-pull-2 col-md-8 col-md-pull-2 col-sm-8 col-sm-pull-2 col-xs-12">
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<div>
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<a id="title" class="mim-anchor"></a>
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<div>
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<a id="number" class="mim-anchor"></a>
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<div class="text-right">
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</div>
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<div>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Gene description">
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<span class="text-danger"><strong>*</strong></span>
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604167
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</span>
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</span>
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</div>
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</div>
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<div>
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<a id="preferredTitle" class="mim-anchor"></a>
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<h3>
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<span class="mim-font">
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CCCTC-BINDING FACTOR; CTCF
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</span>
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</h3>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="alternativeTitles" class="mim-anchor"></a>
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<div>
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<p>
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<span class="mim-font">
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<em>Alternative titles; symbols</em>
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</span>
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</p>
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</div>
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<div>
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<h4>
|
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<span class="mim-font">
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TRANSCRIPTIONAL REPRESSOR CTCF
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</span>
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</h4>
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</div>
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</div>
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<div>
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<br />
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</div>
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</div>
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<div>
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<a id="approvedGeneSymbols" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong><em>HGNC Approved Gene Symbol: <a href="https://www.genenames.org/tools/search/#!/genes?query=CTCF" class="mim-tip-hint" title="HUGO Gene Nomenclature Committee." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'HGNC', 'domain': 'genenames.org'})">CTCF</a></em></strong>
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</span>
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</p>
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</div>
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<div>
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<a id="cytogeneticLocation" class="mim-anchor"></a>
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<p>
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<span class="mim-text-font">
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<strong>
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<em>
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Cytogenetic location: <a href="/geneMap/16/552?start=-3&limit=10&highlight=552">16q22.1</a>
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Genomic coordinates <span class="small">(GRCh38)</span> : <a href="https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&position=chr16:67562526-67639185&dgv=pack&knownGene=pack&omimGene=pack" class="mim-tip-hint" title="UCSC Genome Browser; reference sequences and working draft assemblies for a large collection of genomes." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'UCSC Genome Browser', 'domain': 'genome.ucsc.edu'})">16:67,562,526-67,639,185</a> </span>
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</em>
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</strong>
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<a href="https://www.ncbi.nlm.nih.gov/" target="_blank" class="small"> (from NCBI) </a>
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</span>
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</p>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="geneMap" class="mim-anchor"></a>
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<div style="margin-bottom: 10px;">
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<span class="h4 mim-font">
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<strong>Gene-Phenotype Relationships</strong>
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</span>
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</div>
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<div>
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<table class="table table-bordered table-condensed table-hover small mim-table-padding">
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<thead>
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<tr class="active">
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<th>
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Location
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</th>
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<th>
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Phenotype
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</th>
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<th>
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Phenotype <br /> MIM number
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</th>
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<th>
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Inheritance
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</th>
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<th>
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Phenotype <br /> mapping key
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</th>
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</tr>
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</thead>
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<tbody>
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<tr>
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<td rowspan="1">
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<span class="mim-font">
|
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<a href="/geneMap/16/552?start=-3&limit=10&highlight=552">
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16q22.1
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</a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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Intellectual developmental disorder, autosomal dominant 21
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</span>
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</td>
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<td>
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<span class="mim-font">
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<a href="/entry/615502"> 615502 </a>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="Autosomal dominant">AD</abbr>
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</span>
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</td>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known">3</abbr>
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</span>
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</td>
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</tr>
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</tbody>
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</table>
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</div>
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</div>
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<div>
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<div class="btn-group">
|
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<button type="button" class="btn btn-success dropdown-toggle" data-toggle="dropdown" aria-haspopup="true" aria-expanded="false">
|
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PheneGene Graphics <span class="caret"></span>
|
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</button>
|
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<ul class="dropdown-menu" style="width: 17em;">
|
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<li><a href="/graph/linear/604167" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
|
|
<li><a href="/graph/radial/604167" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
|
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</ul>
|
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</div>
|
|
<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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</div>
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<div>
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<br />
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</div>
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<div>
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<a id="text" class="mim-anchor"></a>
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<h4>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
|
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</span>
|
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</span>
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</h4>
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<div>
|
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<a id="description" class="mim-anchor"></a>
|
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<h4 href="#mimDescriptionFold" id="mimDescriptionToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
|
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<span id="mimDescriptionToggleTriangle" class="small mimTextToggleTriangle">▼</span>
|
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<span class="mim-font">
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<strong>Description</strong>
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</span>
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</h4>
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</div>
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<div id="mimDescriptionFold" class="collapse in ">
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<span class="mim-text-font">
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<p>Transcriptional insulators are DNA elements that set boundaries on the actions of enhancer and silencer elements and thereby organize the eukaryotic genome into regulatory domains (<a href="#27" class="mim-tip-reference" title="Kuhn, E. J., Geyer, P. <strong>Genomic insulators: connecting properties to mechanism.</strong> Curr. Opin. Cell Biol. 15: 259-265, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12787766/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12787766</a>] [<a href="https://doi.org/10.1016/s0955-0674(03)00039-5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12787766">Kuhn and Geyer, 2003</a>). All vertebrate insulators appear to use the versatile CTCF protein. CTCF uses various combinations of its 11 zinc fingers to recognize a variety of unrelated DNA sequences. Once bound to DNA, CTCF can function as a transcriptional insulator, repressor, or activator, depending on the context of the binding site (<a href="#24" class="mim-tip-reference" title="Jeong, S., Pfeifer, K. <strong>Shifting insulator boundaries.</strong> Nature Genet. 36: 1036-1037, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15454938/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15454938</a>] [<a href="https://doi.org/10.1038/ng1004-1036" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15454938">Jeong and Pfeifer, 2004</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?term=15454938+12787766" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#11" class="mim-tip-reference" title="Filippova, G. N., Fagerlie, S., Klenova, E. M., Myers, C., Dehner, Y., Goodwin, G., Neiman, P. E., Collins, S. J., Lobanenkov, V. V. <strong>An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes.</strong> Molec. Cell. Biol. 16: 2802-2813, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8649389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8649389</a>] [<a href="https://doi.org/10.1128/MCB.16.6.2802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8649389">Filippova et al. (1996)</a> isolated and analyzed human CTCF (CCCTC-binding factor) cDNA clones. They showed that the human CTCF protein contains 11 zinc finger domains and is exceptionally highly conserved, sharing 93% identity with the avian CTCF amino acid sequence. CTCF contains 2 transcription repressor domains transferable to a heterologous DNA-binding domain. Northern blot analysis revealed that the human CTCF gene was ubiquitously expressed as an approximately 4-kb transcript. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8649389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#21" class="mim-tip-reference" title="Ideraabdullah, F. Y., Thorvaldsen, J. L., Myers, J. A. <strong>Tissue-specific insulator function at H19/Igf2 revealed by deletions at the imprinting control region.</strong> Hum. Molec. Genet. 23: 6246-6259, 2014.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/24990148/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">24990148</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=24990148[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1093/hmg/ddu344" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="24990148">Ideraabdullah et al. (2014)</a> stated that 7 CTCF protein isoforms migrate at apparent molecular masses ranging from 55 to 130 kD. CTCF can be posttranslationally modified in some tissues by phosphorylation, sumoylation, and poly(ADP-ribosyl)ation. It can also dimerize and multimerize with itself and interact with several protein partners as heterodimers. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=24990148" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>By FISH, <a href="#12" class="mim-tip-reference" title="Filippova, G. N., Lindblom, A., Meincke, L. J., Klenova, E. M., Neiman, P. E., Collins, S. J., Doggett, N. A., Lobanenkov, V. V. <strong>A widely expressed transcription factor with multiple DNA sequence specificity, CTCF, is localized at chromosome segment 16q22.1 within one of the smallest regions of overlap for common deletions in breast and prostate cancers.</strong> Genes Chromosomes Cancer 22: 26-36, 1998.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9591631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9591631</a>]" pmid="9591631">Filippova et al. (1998)</a> mapped the CTCF gene to chromosome 16q22.1 in a small region of overlap for common chromosomal deletions in sporadic breast and prostate tumors, suggesting that CTCF is a candidate tumor suppressor gene. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9591631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<a href="#29" class="mim-tip-reference" title="Li, Y., Haarhuis, J. H. I., Sedeno Cacciatore, A., Oldenkamp, R., van Ruiten, M. S., Willems, L., Teunissen, H., Muir, K. W., de Wit, E., Rowland, B. D., Panne, D. <strong>The structural basis for cohesin-CTCF-anchored loops.</strong> Nature 578: 472-476, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31905366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31905366</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31905366[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-019-1910-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31905366">Li et al. (2020)</a> showed that a segment within the CTCF N terminus interacts with the SA2 (<a href="/entry/300826">300826</a>)-SCC1 (<a href="/entry/600925">600925</a>) subunits of human cohesin. They reported a crystal structure of SA2-SCC1 in complex with CTCF at a resolution of 2.7 angstroms, which revealed the molecular basis of the interaction. <a href="#29" class="mim-tip-reference" title="Li, Y., Haarhuis, J. H. I., Sedeno Cacciatore, A., Oldenkamp, R., van Ruiten, M. S., Willems, L., Teunissen, H., Muir, K. W., de Wit, E., Rowland, B. D., Panne, D. <strong>The structural basis for cohesin-CTCF-anchored loops.</strong> Nature 578: 472-476, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31905366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31905366</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31905366[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-019-1910-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31905366">Li et al. (2020)</a> demonstrated that this interaction is specifically required for CTCF-anchored loops and contributes to the positioning of cohesin at CTCF binding sites. A similar motif is present in a number of established and newly identified cohesin ligands, including the cohesin release factor WAPL (<a href="/entry/610754">610754</a>). <a href="#29" class="mim-tip-reference" title="Li, Y., Haarhuis, J. H. I., Sedeno Cacciatore, A., Oldenkamp, R., van Ruiten, M. S., Willems, L., Teunissen, H., Muir, K. W., de Wit, E., Rowland, B. D., Panne, D. <strong>The structural basis for cohesin-CTCF-anchored loops.</strong> Nature 578: 472-476, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31905366/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31905366</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31905366[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-019-1910-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31905366">Li et al. (2020)</a> concluded that their data suggested that CTCF enables the formation of chromatin loops by protecting cohesin against loop release. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31905366" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p><a href="#11" class="mim-tip-reference" title="Filippova, G. N., Fagerlie, S., Klenova, E. M., Myers, C., Dehner, Y., Goodwin, G., Neiman, P. E., Collins, S. J., Lobanenkov, V. V. <strong>An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes.</strong> Molec. Cell. Biol. 16: 2802-2813, 1996.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8649389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8649389</a>] [<a href="https://doi.org/10.1128/MCB.16.6.2802" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="8649389">Filippova et al. (1996)</a> found that CTCF bound specifically to regulatory sequences in the promoter-proximal regions of chicken, mouse, and human MYC (<a href="/entry/190080">190080</a>) oncogenes. One CTCF-binding site, conserved in mouse and human MYC genes, was found immediately downstream of the major P2 promoter. Gel shift assays of nuclear extracts from mouse and human cells showed that CTCF was the predominant factor binding to this sequence. Mutation analysis of the P2-proximal CTCF-binding site and transient cotransfection experiments demonstrated that CTCF transcriptionally repressed the human MYC gene. Although there is 100% sequence identity in the DNA-binding domains of the avian and human CTCF proteins, the regulatory sequences recognized by CTCF in chicken and human MYC promoters were clearly diverged. Mutating the contact nucleotides confirmed that CTCF binding to the P2 promoter of the human MYC gene required a number of unique contact DNA bases that were absent in the CTCF-binding site of the chicken MYC gene. Moreover, proteolytic protection assays indicated that several more CTCF zinc fingers were involved in contacting the human CTCF-binding site than the chicken site. Gel shift assays utilizing successively deleted zinc finger domains indicated that CTCF zinc fingers 2 to 7 were involved in binding to the chicken MYC promoter, while fingers 3 to 11 mediated CTCF binding to the human promoter. This flexibility in zinc finger usage revealed CTCF to be a 'multivalent' transcription factor. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8649389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="Bell, A. C., West, A. G., Felsenfeld, G. <strong>The protein CTCF is required for the enhancer blocking activity of vertebrate insulators.</strong> Cell 98: 387-396, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10458613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10458613</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81967-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10458613">Bell et al. (1999)</a> identified a 42-bp DNA fragment of the chicken beta-globin insulator that is both necessary and sufficient for enhancer-blocking activity in human cells. They showed that this sequence, FII, is the binding site for CTCF, and these CTCF-binding sites were present in all of the vertebrate enhancer-blocking elements examined. <a href="#4" class="mim-tip-reference" title="Bell, A. C., West, A. G., Felsenfeld, G. <strong>The protein CTCF is required for the enhancer blocking activity of vertebrate insulators.</strong> Cell 98: 387-396, 1999.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10458613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10458613</a>] [<a href="https://doi.org/10.1016/s0092-8674(00)81967-4" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10458613">Bell et al. (1999)</a> suggested that directional enhancer blocking by CTCF is a conserved component of gene regulation in vertebrates. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10458613" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#3" class="mim-tip-reference" title="Bell, A. C., Felsenfeld, G. <strong>Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene.</strong> Nature 405: 482-485, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839546</a>] [<a href="https://doi.org/10.1038/35013100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839546">Bell and Felsenfeld (2000)</a> and <a href="#19" class="mim-tip-reference" title="Hark, A. T., Schoenherr, C. J., Katz, D. J., Ingram, R. S., Levrose, J. M., Tilghman, S. M. <strong>CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus.</strong> Nature 405: 486-489, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839547</a>] [<a href="https://doi.org/10.1038/35013106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839547">Hark et al. (2000)</a> independently showed that CTCF binds to several sites within the unmethylated imprinted-control region (ICR1; <a href="/entry/616186">616186</a>) between H19 (<a href="/entry/103280">103280</a>) and IGF2 (<a href="/entry/147470">147470</a>) that are essential for enhancer blocking. <a href="#19" class="mim-tip-reference" title="Hark, A. T., Schoenherr, C. J., Katz, D. J., Ingram, R. S., Levrose, J. M., Tilghman, S. M. <strong>CTCF mediates methylation-sensitive enhancer-blocking activity at the H19/Igf2 locus.</strong> Nature 405: 486-489, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839547/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839547</a>] [<a href="https://doi.org/10.1038/35013106" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839547">Hark et al. (2000)</a> demonstrated that CTCF binding is abolished by DNA methylation of ICR1. Methylation of the CpGs within the CTCF binding sites eliminates binding of CTCF in vitro, and deletion of these sites results in loss of enhancer-blocking activity in vivo, thereby allowing gene expression. This CTCF-dependent enhancer-blocking element acts as an insulator. <a href="#3" class="mim-tip-reference" title="Bell, A. C., Felsenfeld, G. <strong>Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene.</strong> Nature 405: 482-485, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839546</a>] [<a href="https://doi.org/10.1038/35013100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839546">Bell and Felsenfeld (2000)</a> suggested that it controls imprinting of IGF2 and that activity of this insulator is restricted to the maternal allele by specific DNA methylation of the paternal allele. <a href="#3" class="mim-tip-reference" title="Bell, A. C., Felsenfeld, G. <strong>Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene.</strong> Nature 405: 482-485, 2000.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839546</a>] [<a href="https://doi.org/10.1038/35013100" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="10839546">Bell and Felsenfeld (2000)</a> concluded that DNA methylation can control gene expression by modulating enhancer access to the gene promoter through regulation of an enhancer boundary. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=10839546+10839547" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>An expansion of a CTG repeat at the DM1 locus causes myotonic dystrophy by altering the expression of 2 adjacent genes, DMPK (<a href="/entry/605377">605377</a>) and SIX5 (<a href="/entry/600963">600963</a>) and through a toxic effect of the repeat-containing RNA. <a href="#13" class="mim-tip-reference" title="Filippova, G. N., Thienes, C. P., Penn, B. H., Cho, D. H., Hu, Y. J., Moore, J. M., Klesert, T. R., Lobanenkov, V. V., Tapscott, S. J. <strong>CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus.</strong> Nature Genet. 28: 335-343, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479593</a>] [<a href="https://doi.org/10.1038/ng570" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479593">Filippova et al. (2001)</a> identified 2 CTCF binding sites that flank the CTG repeat and form an insulator element between DMPK and SIX5. Methylation of these sites prevents binding of CTCF, indicating that the DM1 locus methylation in congenital myotonic dystrophy would disrupt insulator function. Furthermore, CTCF binding sites are associated with CTG/CAG repeats at several other loci. <a href="#13" class="mim-tip-reference" title="Filippova, G. N., Thienes, C. P., Penn, B. H., Cho, D. H., Hu, Y. J., Moore, J. M., Klesert, T. R., Lobanenkov, V. V., Tapscott, S. J. <strong>CTCF-binding sites flank CTG/CAG repeats and form a methylation-sensitive insulator at the DM1 locus.</strong> Nature Genet. 28: 335-343, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479593</a>] [<a href="https://doi.org/10.1038/ng570" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11479593">Filippova et al. (2001)</a> suggested a general role for CTG/CAG repeats as components of insulator elements at multiple sites in the human genome. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479593" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Chao, W., Huynh, K. D., Spencer, R. J., Davidow, L. S., Lee, J. T. <strong>CTCF, a candidate trans-acting factor for X-inactivation choice.</strong> Science 295: 345-347, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11743158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11743158</a>] [<a href="https://doi.org/10.1126/science.1065982" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11743158">Chao et al. (2002)</a> identified the insulator and transcription factor CTCF as a candidate trans-acting factor for X chromosome selection in mouse. The choice/imprinting center contains tandem CTCF binding sites that function in an enhancer-blocking assay. In vitro binding is reduced by CpG methylation and abolished by including non-CpG methylation. <a href="#6" class="mim-tip-reference" title="Chao, W., Huynh, K. D., Spencer, R. J., Davidow, L. S., Lee, J. T. <strong>CTCF, a candidate trans-acting factor for X-inactivation choice.</strong> Science 295: 345-347, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11743158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11743158</a>] [<a href="https://doi.org/10.1126/science.1065982" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11743158">Chao et al. (2002)</a> postulated that Tsix (<a href="/entry/300181">300181</a>) and CTCF together establish a regulatable epigenetic switch for X inactivation. Murine Tsix contains greater than 40 CTCF motifs, and the human sequence has greater than 10. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11743158" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Two noncoding loci, TSIX and XIST (<a href="/entry/314670">314670</a>), regulate X chromosome inactivation by controlling homologous chromosome pairing, counting, and choice of chromosome to be inactivated. <a href="#9" class="mim-tip-reference" title="Donohoe, M. E., Zhang, L.-F., Xu, N., Shi, Y., Lee, J. T. <strong>Identification of a Ctcf cofactor, Yy1, for the X chromosome binary switch.</strong> Molec. Cell 25: 43-56, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17218270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17218270</a>] [<a href="https://doi.org/10.1016/j.molcel.2006.11.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17218270">Donohoe et al. (2007)</a> found that paired Ctcf-Yy1 (<a href="/entry/600013">600013</a>) elements are highly clustered within the counting/choice and imprinting domain of mouse Tsix, and they stated that similar clustering of paired YY1-CTCF sites occurs in the human X inactivation center. Immunoprecipitation and protein pull-down experiments showed direct binding between Ctcf and Yy1, and mutation analysis demonstrated that the highest affinity interactions occurred between the zinc finger of Yy1 and the N terminus of Ctcf. <a href="#9" class="mim-tip-reference" title="Donohoe, M. E., Zhang, L.-F., Xu, N., Shi, Y., Lee, J. T. <strong>Identification of a Ctcf cofactor, Yy1, for the X chromosome binary switch.</strong> Molec. Cell 25: 43-56, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17218270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17218270</a>] [<a href="https://doi.org/10.1016/j.molcel.2006.11.017" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17218270">Donohoe et al. (2007)</a> found that Yy1 +/- mouse embryonic stem cells had inappropriate Tsix downregulation and Xist upregulation, and knockdown of Ctcf through RNA interference yielded an identical phenotype. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17218270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Through combinatorial use of its 11 zinc fingers, CTCF binds to target sites of approximately 50 bp that have remarkable sequence variation. The formation of different CTCF-DNA complexes, some of which are methylation-sensitive, results in distinct functions, including gene activation, repression, silencing, and chromatin insulation. Disruption of the spectrum of target specificities by zinc finger mutations or by abnormal selective methylation of targets is associated with cancer. <a href="#34" class="mim-tip-reference" title="Ohlsson, R., Renkawitz, R., Lobanenkov, V. <strong>CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease.</strong> Trends Genet. 17: 520-527, 2001.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11525835/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11525835</a>] [<a href="https://doi.org/10.1016/s0168-9525(01)02366-6" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="11525835">Ohlsson et al. (2001)</a> stated that CTCF is a tumor suppressor gene. The role of CTCF in imprinting, however, suggested a functional richness not associated with other tumor suppressor genes. A crucial role for CTCF in natural selection was also suggested, because it relates to induction of functional and stable hemizygosity for expression of certain genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11525835" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Normally, CTCF and the CTCF paralog BORIS (CTCFL; <a href="/entry/607022">607022</a>) are expressed in a mutually exclusive pattern that correlates with resetting of methylation marks during male germ cell differentiation. The suggestion that BORIS directs epigenetic programming at CTCF target sites impinges on the observations that human BORIS is not only abnormally activated in a wide range of human cancers, but also maps to the cancer-associated amplification region at chromosome 20q13. <a href="#25" class="mim-tip-reference" title="Klenova, E. M., Morse, H. C., III, Ohlsson, R., Lobanenkov, V. V. <strong>The novel BORIS + CTCF gene family is uniquely involved in the epigenetics of normal biology and cancer.</strong> Semin. Cancer Biol. 12: 399-414, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12191639/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12191639</a>] [<a href="https://doi.org/10.1016/s1044-579x(02)00060-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12191639">Klenova et al. (2002)</a> suggested that the rivalry occasioned by aberrant expression of BORIS in cancer may interfere with normal functions of CTCF, including growth repression, and contribute to epigenetic dysregulation, which is a common feature in human cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12191639" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#23" class="mim-tip-reference" title="Ishihara, K., Sasaki, H. <strong>An evolutionarily conserved putative insulator element near the 3-prime boundary of the imprinted Igf2/H19 domain.</strong> Hum. Molec. Genet. 11: 1627-1636, 2002.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12075007/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12075007</a>] [<a href="https://doi.org/10.1093/hmg/11.14.1627" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12075007">Ishihara and Sasaki (2002)</a> identified a binding site for CTCF in the intergenic region between H19 and L23mrp on mouse chromosome 7. This site is conserved between human and mouse, associated with a major DNase I-hypersensitive site, and bound by CTCF in vivo. Functional assays using reporter constructs demonstrated that this element may function as an insulator for the 3-prime boundary of this imprinted domain. The authors hypothesized that CTCF-dependent insulators may not only regulate but also delimit the imprinted domain. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12075007" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Although the essential DNA methyltransferases had been discovered, proteins that regulate the sequence-specific establishment and maintenance of allelic methylation had not been identified. One candidate regulator of methylation was the zinc finger protein CTCF, which binds to the imprinting control region (ICR) of the genes IGF2 and H19. The unmethylated maternal ICR is a chromatin boundary that prevents distant enhancers from activating IGF2. In vitro experiments had suggested that CTCF mediates boundary activity of the maternal ICR, and that methylation of the paternal ICR abolishes this activity by preventing CTCF binding. Using mice with point mutations in all 4 CTCF sites in the ICR, <a href="#35" class="mim-tip-reference" title="Schoenherr, C. J., Levorse, J. M., Tilghman, S. M. <strong>CTCF maintains differential methylation at the Igf2/H19 locus.</strong> Nature Genet. 33: 66-69, 2003.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12461525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12461525</a>] [<a href="https://doi.org/10.1038/ng1057" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="12461525">Schoenherr et al. (2003)</a> showed that maternally transmitted mutant ICRs in neonatal mice acquired a substantial but heterogeneous degree of methylation. Mutant ICRs in oocytes and blastocysts were not methylated, however, indicating that binding of CTCF is not required to establish the unmethylated ICR during oogenesis. The authors also showed that the mutant ICR lacked enhancer-blocking activity, as the expression of IGF2 is activated on mutant maternal chromosomes. Conversely, maternal H19 expression was reduced, suggesting a positive role for CTCF in the transcription of that gene. This was said to be the first in vivo demonstration of the multiple functions of CTCF in an ICR. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12461525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#10" class="mim-tip-reference" title="Fedoriw, A. M., Stein, P., Svoboda, P., Schultz, R. M., Bartolomei, M. S. <strong>Transgenic RNAi reveals essential function for CTCF in H19 gene imprinting.</strong> Science 303: 238-240, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14716017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14716017</a>] [<a href="https://doi.org/10.1126/science.1090934" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14716017">Fedoriw et al. (2004)</a> used a transgenic RNA interference (RNAi)-based approach to generate oocytes with reduced amounts of CTCF protein, and found increased methylation of the H19 differentially methylated domain and decreased developmental competence of CTCF-deficient oocytes. <a href="#10" class="mim-tip-reference" title="Fedoriw, A. M., Stein, P., Svoboda, P., Schultz, R. M., Bartolomei, M. S. <strong>Transgenic RNAi reveals essential function for CTCF in H19 gene imprinting.</strong> Science 303: 238-240, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14716017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14716017</a>] [<a href="https://doi.org/10.1126/science.1090934" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="14716017">Fedoriw et al. (2004)</a> concluded that CTCF protects H19 differentially methylated domain from de novo methylation during oocyte growth and is required for normal preimplantation development. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14716017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#43" class="mim-tip-reference" title="Yu, W., Ginjala, V., Pant, V., Chernukhin, I., Whitehead, J., Docquier, F., Farrar, D., Tavoosidana, G., Mukhopadhyay, R., Kanduri, C., Oshimura, M., Feinberg, A. P., Lobanenkov, V., Klenova, E., Ohlsson, R. <strong>Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation.</strong> Nature Genet. 36: 1105-1110, 2004.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15361875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15361875</a>] [<a href="https://doi.org/10.1038/ng1426" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="15361875">Yu et al. (2004)</a> identified poly(ADP-ribosyl)ation as a posttranslational mechanism for regulating CTCF insulator activity that adds to its versatility and its ability to effectively manage epigenetic programs. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15361875" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Gene transcription may be regulated by remote enhancer or insulator regions through chromosome looping. Using a modification of chromosome conformation capture and fluorescence in situ hybridization, <a href="#30" class="mim-tip-reference" title="Ling, J. Q., Li, T., Hu, J. F., Vu, T. H., Chen, H. L., Qiu, X. W., Cherry, A. M., Hoffman, A. R. <strong>CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1.</strong> Science 312: 269-272, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16614224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16614224</a>] [<a href="https://doi.org/10.1126/science.1123191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16614224">Ling et al. (2006)</a> found that 1 allele of the Igf2/H19 ICR on mouse chromosome 7 colocalized with 1 allele of Wsb1 (<a href="/entry/610091">610091</a>)/Nf1 (<a href="/entry/613113">613113</a>) on mouse chromosome 11. Omission of Ctcf or deletion of the maternal ICR abrogated this association and altered Wsb1/Nf1 gene expression. <a href="#30" class="mim-tip-reference" title="Ling, J. Q., Li, T., Hu, J. F., Vu, T. H., Chen, H. L., Qiu, X. W., Cherry, A. M., Hoffman, A. R. <strong>CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1.</strong> Science 312: 269-272, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16614224/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16614224</a>] [<a href="https://doi.org/10.1126/science.1123191" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16614224">Ling et al. (2006)</a> concluded that their findings demonstrated that CTCF mediates an interchromosomal association, perhaps by directing distant DNA segments to a common transcription factory, and the data provided a model for long-range allele-specific associations between gene regions on different chromosomes that suggested a framework for DNA recombination and RNA trans-splicing. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16614224" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using embryonic mouse erythroid progenitor cells, <a href="#39" class="mim-tip-reference" title="Splinter, E., Heath, H., Kooren, J., Palstra, R.-J., Klous, P., Grosveld, F., Galjart, N., de Laat, W. <strong>CTCF mediates long-range chromatin looping and local histone modification in the beta-globin locus.</strong> Genes Dev. 20: 2349-2354, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16951251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16951251</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16951251[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1101/gad.399506" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16951251">Splinter et al. (2006)</a> showed that Ctcf interacted with Ctcf-binding sites in the beta-globin locus (<a href="/entry/141900">141900</a>). Conditional deletion of Ctcf and targeted disruption of a DNA-binding site destabilized these long-range interactions and caused local loss of histone acetylation and gain of histone methylation, apparently without affecting transcription at the locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16951251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using yeast 2-hybrid analysis and pull-down assays, <a href="#22" class="mim-tip-reference" title="Ishihara, K., Oshimura, M., Nakao, M. <strong>CTCF-dependent chromatin insulator is linked to epigenetic remodeling.</strong> Molec. Cell 23: 733-742, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16949368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16949368</a>] [<a href="https://doi.org/10.1016/j.molcel.2006.08.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16949368">Ishihara et al. (2006)</a> found that the C-terminal region of mouse Chd8 (<a href="/entry/610528">610528</a>) interacted with the zinc finger domain of Ctcf. Chromatin immunoprecipitation analysis of a human hepatoma cell line revealed that CHD8 was present at CTCF target sites, such as the differentially methylated region of H19, the locus control region of beta-globin, and the promoter regions of the BRCA1 (<a href="/entry/113705">113705</a>) and MYC genes. Immunoprecipitation analysis demonstrated an endogenous complex of CHD8 and CTCF in HeLa cells. Knockdown of CHD8 in HeLa cells by RNA interference abolished the CTCF-dependent insulator activity of the H19 differentially methylated region, leading to reactivation of imprinted IGF2 from the maternal chromosome. Lack of CHD8 affected CpG methylation and histone acetylation around the CTCF-binding sites, which are adjacent to heterochromatin, of the BRCA1 and MYC genes. <a href="#22" class="mim-tip-reference" title="Ishihara, K., Oshimura, M., Nakao, M. <strong>CTCF-dependent chromatin insulator is linked to epigenetic remodeling.</strong> Molec. Cell 23: 733-742, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16949368/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16949368</a>] [<a href="https://doi.org/10.1016/j.molcel.2006.08.008" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="16949368">Ishihara et al. (2006)</a> concluded that CTCF-CHD8 has a role in insulation and epigenetic regulation at active insulator sites. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16949368" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#1" class="mim-tip-reference" title="Akopov, S. B., Ruda, V. M., Batrak, V. V., Vetchinova, A. S., Chernov, I. P., Nikolaev, L. G., Bode, J., Sverdlov, E. D. <strong>Identification, genome mapping, and CTCF binding of potential insulators within the FXYD5-COX7A1 locus of human chromosome 19q13.12.</strong> Mammalian Genome 17: 1042-1049, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17019650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17019650</a>] [<a href="https://doi.org/10.1007/s00335-006-0037-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17019650">Akopov et al. (2006)</a> suggested an approach that allowed direct isolation of insulators by a simple positive-negative selection based on blocking enhancer effects by insulators. The approach allowed selection of fragments capable of blocking enhancers from mixtures of genomic fragments prepared from genomic regions of up to 1 Mb. Using this approach, a 1-Mb human genome locus was analyzed, the FXYD5 (<a href="/entry/606669">606669</a>)/COX7A1 (<a href="/entry/123995">123995</a>) locus on 19q13.13. The genes ATP4A (<a href="/entry/137216">137216</a>) and APLP1 (<a href="/entry/104775">104775</a>) within the locus studied were found to be flanked by insulators on both sides. Both genes are characterized by distinct tissue-specific expression that differs from the tissue specificity of the surrounding genes. The data were considered consistent with the concept that insulators subdivide genomic DNA into loop domains that comprise genes characterized by similar expression profiles. Using chromatin immunoprecipitation assay, <a href="#1" class="mim-tip-reference" title="Akopov, S. B., Ruda, V. M., Batrak, V. V., Vetchinova, A. S., Chernov, I. P., Nikolaev, L. G., Bode, J., Sverdlov, E. D. <strong>Identification, genome mapping, and CTCF binding of potential insulators within the FXYD5-COX7A1 locus of human chromosome 19q13.12.</strong> Mammalian Genome 17: 1042-1049, 2006.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17019650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17019650</a>] [<a href="https://doi.org/10.1007/s00335-006-0037-3" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17019650">Akopov et al. (2006)</a> demonstrated also that at least 6 of the putative insulators revealed in this work could bind the CTCF transcription factor in vivo. They believed that the proposed approach could be a useful instrument for functional analysis of genomes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17019650" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>X-chromosome inactivation ensures the equality of X-chromosome dosages in male and female mammals by silencing one X in the female (<a href="#31" class="mim-tip-reference" title="Lyon, M. F. <strong>Gene action in the X-chromosome of the mouse (Mus musculus L.).</strong> Nature 190: 372-373, 1961.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/13764598/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">13764598</a>] [<a href="https://doi.org/10.1038/190372a0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="13764598">Lyon, 1961</a>). To achieve the mutually exclusive designation of active X (Xa) and inactive X (Xi), the process necessitates that 2 Xs communicate in trans through homologous pairing. Pairing depends on a 15-kb region within the genes TSIX (<a href="/entry/300181">300181</a>) and XITE (<a href="/entry/300074">300074</a>). <a href="#42" class="mim-tip-reference" title="Xu, N., Donohoe, M. E., Silva, S. S., Lee, J. T. <strong>Evidence that homologous X-chromosome pairing requires transcription and Ctcf protein.</strong> Nature Genet. 39: 1390-1396, 2007.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17952071/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17952071</a>] [<a href="https://doi.org/10.1038/ng.2007.5" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="17952071">Xu et al. (2007)</a> dissected the molecular requirements by transgenic methods in mouse cells and found that pairing can be recapitulated by a 1- to 2-kb subfragment of Tsix or Xite with little sequence similarity. However, a common denominator among them was the presence of the protein Ctcf, a chromatin insulator that they found to be essential for pairing. Pairing also depended on transcription. Transcriptional inhibition prevented new pair formation but did not perturb existing pairs. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=13764598+17952071" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#41" class="mim-tip-reference" title="Wendt, K. S., Yoshida, K., Itoh, T., Bando, M., Koch, B., Schirghuber, E., Tsutsumi, S., Nagae, G., Ishihara, K., Mishiro, T., Yahata, K., Imamoto, F., Aburatani, H., Nakao, M., Imamoto, N., Maeshima, K., Shirahige, K., Peters, J.-M. <strong>Cohesin mediates transcriptional insulation by CCCTC-binding factor.</strong> Nature 451: 796-801, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18235444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18235444</a>] [<a href="https://doi.org/10.1038/nature06634" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18235444">Wendt et al. (2008)</a> described cohesin-binding sites in the human genome and showed that most of these are associated with CTCF, a zinc finger protein required for transcriptional insulation. CTCF is dispensable for cohesin loading onto DNA, but is needed to enrich cohesin at specific binding sites. Cohesin enables CTCF to insulate promoters from distant enhancers and controls transcription at the H19/IGF2 locus. This role of cohesin seems to be independent of its role in cohesion. <a href="#41" class="mim-tip-reference" title="Wendt, K. S., Yoshida, K., Itoh, T., Bando, M., Koch, B., Schirghuber, E., Tsutsumi, S., Nagae, G., Ishihara, K., Mishiro, T., Yahata, K., Imamoto, F., Aburatani, H., Nakao, M., Imamoto, N., Maeshima, K., Shirahige, K., Peters, J.-M. <strong>Cohesin mediates transcriptional insulation by CCCTC-binding factor.</strong> Nature 451: 796-801, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18235444/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18235444</a>] [<a href="https://doi.org/10.1038/nature06634" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18235444">Wendt et al. (2008)</a> proposed that cohesin functions as a transcriptional insulator, and speculated that subtle deficiencies in this function contribute to 'cohesinopathies' such as Cornelia de Lange syndrome (see <a href="/entry/122470">122470</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18235444" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#32" class="mim-tip-reference" title="Majumder, P., Gomez, J. A., Chadwick, B. P., Boss, J. M. <strong>The insulator factor CTCF controls MHC class II gene expression and is required for the formation of long-distance chromatin interactions.</strong> J. Exp. Med. 205: 785-798, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18347100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18347100</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18347100[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20071843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18347100">Majumder et al. (2008)</a> found that small interfering RNA-mediated knockdown of CTCF, which binds XL9, an intergenic element between HLA-DRB1 (<a href="/entry/142857">142857</a>) and HLA-DQA1 (<a href="/entry/146880">146880</a>), reduced DRB1 and DQA1 expression. Coimmunoprecipitation experiments showed that CTCF, CIITA (MHC2TA; <a href="/entry/600005">600005</a>), and RFX5 (<a href="/entry/601863">601863</a>) were in the same complex, suggesting that XL9 and the DRB1 and DQA1 proximal promoters may interact. Chromatin conformation capture (3C) analysis indicated that this was likely the case, and the 3C product was lost by knockdown of CTCF. RNA FISH analysis showed that both DRB1 and DQA1 could be expressed simultaneously in some cells. <a href="#32" class="mim-tip-reference" title="Majumder, P., Gomez, J. A., Chadwick, B. P., Boss, J. M. <strong>The insulator factor CTCF controls MHC class II gene expression and is required for the formation of long-distance chromatin interactions.</strong> J. Exp. Med. 205: 785-798, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18347100/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18347100</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18347100[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1084/jem.20071843" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18347100">Majumder et al. (2008)</a> concluded that CTCF interactions represent a novel mechanism for the regulation of these immune system major histocompatibility complex genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18347100" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#20" class="mim-tip-reference" title="Heintzman, N. D., Hon, G. C., Hawkins, R. D., Kheradpour, P., Stark, A., Harp, L. F., Ye, Z., Lee, L. K., Stuart, R. K., Ching, C. W., Ching, K. A., Antosiewicz-Bourget, J. E., and 9 others. <strong>Histone modifications at human enhancers reflect global cell-type-specific gene expression.</strong> Nature 459: 108-112, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19295514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19295514</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19295514[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19295514">Heintzman et al. (2009)</a> used a chromatin immunoprecipitation-based microarray method (ChIP-chip) to identify promoters, enhancers, and insulators in multiple cell types and investigate their roles in cell type-specific gene expression. They observed that the chromatin state at promoters and CTCF binding at insulators is largely invariant across diverse cell types. In contrast, enhancers are marked by highly cell type-specific histone modification patterns, strongly correlate to cell type-specific gene expression programs on a global scale, and are functionally active in a cell type-specific manner. <a href="#20" class="mim-tip-reference" title="Heintzman, N. D., Hon, G. C., Hawkins, R. D., Kheradpour, P., Stark, A., Harp, L. F., Ye, Z., Lee, L. K., Stuart, R. K., Ching, C. W., Ching, K. A., Antosiewicz-Bourget, J. E., and 9 others. <strong>Histone modifications at human enhancers reflect global cell-type-specific gene expression.</strong> Nature 459: 108-112, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19295514/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19295514</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19295514[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07829" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19295514">Heintzman et al. (2009)</a> concluded that their results defined over 55,000 potential transcriptional enhancers in the human genome, significantly expanding the current catalog of human enhancers and highlighting the role of these elements in cell type-specific gene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19295514" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#17" class="mim-tip-reference" title="Hadjur, S., Williams, L. M., Ryan, N. K., Cobb, B. S., Sexton, T., Fraser, P., Fisher, A. G., Merkenschlager, M. <strong>Cohesins form chromosomal cis-interactions at the developmentally regulated IFNG locus.</strong> Nature 460: 410-413, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19458616/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19458616</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19458616[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08079" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19458616">Hadjur et al. (2009)</a> showed that cohesin/CTCF formed the topologic and mechanistic basis for cell type-specific, long-range chromosomal interactions in cis at the developmentally regulated cytokine locus IFNG (<a href="/entry/147570">147570</a>) by associating with a select set of conserved sequence elements. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19458616" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#8" class="mim-tip-reference" title="Donohoe, M. E., Silva, S. S., Pinter, S. F., Xu, N., Lee, J. T. <strong>The pluripotency factor Oct4 interacts with Ctcf and also controls X-chromosome pairing and counting.</strong> Nature 460: 128-132, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19536159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19536159</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19536159[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19536159">Donohoe et al. (2009)</a> demonstrated that OCT4 (<a href="/entry/164177">164177</a>) lies at the top of the X chromosome inactivation (XCI) hierarchy and regulates XCI by triggering X chromosome pairing and counting. OCT4 directly binds TSIX (<a href="/entry/300181">300181</a>) and XITE (<a href="/entry/300074">300074</a>), 2 regulatory noncoding RNA genes of the X inactivation center, and also complexes with SCI transfactors CTCF and YY1 (<a href="/entry/600013">600013</a>) through protein-protein interactions. Depletion of Oct4 blocked homologous X-chromosome pairing and resulted in the inactivation of both X chromosomes in female mouse embryonic stem cells. <a href="#8" class="mim-tip-reference" title="Donohoe, M. E., Silva, S. S., Pinter, S. F., Xu, N., Lee, J. T. <strong>The pluripotency factor Oct4 interacts with Ctcf and also controls X-chromosome pairing and counting.</strong> Nature 460: 128-132, 2009.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19536159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19536159</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19536159[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature08098" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="19536159">Donohoe et al. (2009)</a> concluded that they identified the first trans-factor that regulates counting, and ascribed new functions to OCT4 during X-chromosome reprogramming. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19536159" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>Using chromatin immunoprecipitation sequencing (ChIP-Seq), <a href="#28" class="mim-tip-reference" title="Kunarso, G., Chia, N.-Y., Jeyakani, J., Hwang, C., Lu, X., Chan, Y.-S., Ng, H.-H., Bourque, G. <strong>Transposable elements have rewired the core regulatory network of human embryonic stem cells.</strong> Nature Genet. 42: 631-634, 2010.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/20526341/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">20526341</a>] [<a href="https://doi.org/10.1038/ng.600" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="20526341">Kunarso et al. (2010)</a> showed that genomic regions bound by CTCF were highly conserved between undifferentiated mouse and human embryonic stem cells. However, very little conservation was found for regions bound by OCT4 and NANOG (<a href="/entry/607937">607937</a>). Most of the differences in OCT4 and NANOG binding between species appeared to be due to species-specific insertion of transposable elements, such as endogenous ERV1 repeats, that generated unique OCT4- and NANOG-repeat-associated binding sites. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=20526341" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#18" class="mim-tip-reference" title="Handoko, L., Xu, H., Li, G., Ngan, C. Y., Chew, E., Schnapp, M., Lee, C. W. H., Ye, C., Ping, J. L. H., Mulawadi, F., Wong, E., Sheng, J., and 10 others. <strong>CTCF-mediated functional chromatin interactome in pluripotent cells.</strong> Nature Genet. 43: 630-638, 2011. Note: Erratum: Nature Genet. 43: 815 only, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21685913/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21685913</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21685913[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ng.857" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21685913">Handoko et al. (2011)</a> characterized global Ctcf-associated chromatin organization in mouse embryonic stem cells and identified 1,480 intrachromosomal and 336 interchromosomal interactions with high confidence. Examination of histone methylation patterns, binding of RNA polymerase II (see <a href="/entry/180660">180660</a>) or p300 enhancer (EP300; <a href="/entry/602700">602700</a>), and nuclear lamina occupancy revealed 5 categories of intrachromosomal loops: loops with active characteristics, loops with repressive characteristics, loops functioning as hubs for enhancer and promoter activities, loops with opposite chromatin states flanking the boundaries, and loops lacking specific chromatin patterns. Loops of over 200 kb were more likely to be associated with active characteristics, while those of less than 200 kb were more likely to be silent. Lamin B (LMNB1; <a href="/entry/150340">150340</a>)-associated loops appeared to act as insulators. Ctcf-mediated looping also brought the promoters of a number of genes into close contact (less than 10 kb) with p300 and enhanced gene expression. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21685913" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#16" class="mim-tip-reference" title="Guo, C., Yoon, H. S., Franklin, A., Jain, S., Ebert, A., Cheng, H.-L., Hansen, E., Despo, O., Bossen, C., Vettermann, C., Bates, J. G., Richards, N., Myers, D., Patel, H., Gallagher, M., Schlissel, M. S., Murre, C., Busslinger, M., Giallourakis, C. C., Alt, F. W. <strong>CTCF-binding elements mediate control of V(D)J recombination.</strong> Nature 477: 424-430, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21909113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21909113</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21909113[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21909113">Guo et al. (2011)</a> reported in mice a key immunoglobulin heavy chain (Igh; see <a href="/entry/147100">147100</a>) V(D)J recombination regulatory region, termed intergenic control region-1 (IGCR1), which lies between the V(H) and D clusters. Functionally, IGCR1 uses CTCF looping/insulator factor-binding elements and correspondingly mediates Igh loops containing distant enhancers. IGCR1 promotes normal B-cell development and balances antibody repertoires by inhibiting transcription and rearrangement of D(H)-proximal V(H) gene segments and promoting rearrangement of distal V(H) segments. IGCR1 maintains ordered and lineage-specific V(H)(D)J(H) recombination by suppressing V(H) joining to D segments not joined to J(H) segments, and V(H) to DJ(H) joins in thymocytes, respectively. IGCR1 is also required for feedback regulation and allelic exclusion of proximal V(H)-to-DJ(H) recombination. <a href="#16" class="mim-tip-reference" title="Guo, C., Yoon, H. S., Franklin, A., Jain, S., Ebert, A., Cheng, H.-L., Hansen, E., Despo, O., Bossen, C., Vettermann, C., Bates, J. G., Richards, N., Myers, D., Patel, H., Gallagher, M., Schlissel, M. S., Murre, C., Busslinger, M., Giallourakis, C. C., Alt, F. W. <strong>CTCF-binding elements mediate control of V(D)J recombination.</strong> Nature 477: 424-430, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21909113/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21909113</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21909113[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10495" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21909113">Guo et al. (2011)</a> concluded that their studies elucidated a long-sought Igh V(D)J recombination control region and indicated a new role for the generally expressed CTCF protein. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21909113" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#37" class="mim-tip-reference" title="Shukla, S., Kavak, E., Gregory, M., Imashimizu, M., Shutinoski, B., Kashlev, M., Oberdoerffer, P., Sandberg, R., Oberdoerffer, S. <strong>CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing.</strong> Nature 479: 74-79, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964334</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21964334[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964334">Shukla et al. (2011)</a> provided evidence that CTCF can promote inclusion of weak upstream exons by mediating local RNA polymerase II pausing both in a mammalian model system for alternative splicing, CD45 (<a href="/entry/151460">151460</a>), and genomewide. They further showed that CTCF binding to CD45 exon 5 is inhibited by DNA methylation, leading to reciprocal effects on exon 5 inclusion. <a href="#37" class="mim-tip-reference" title="Shukla, S., Kavak, E., Gregory, M., Imashimizu, M., Shutinoski, B., Kashlev, M., Oberdoerffer, P., Sandberg, R., Oberdoerffer, S. <strong>CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing.</strong> Nature 479: 74-79, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964334</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21964334[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature10442" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21964334">Shukla et al. (2011)</a> concluded that their results provided a mechanistic basis for developmental regulation of splicing outcome through heritable epigenetic marks. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21964334" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#38" class="mim-tip-reference" title="Sopher, B. L., Ladd, P. D., Pineda, V. V., Libby, R. T., Sunkin, S. M., Hurley, J. B., Thienes, C. P., Gaasterland, T., Filippova, G. N., La Spada, A. R. <strong>CTCF regulates ataxin-7 expression through promotion of a convergently transcribed, antisense noncoding RNA.</strong> Neuron 70: 1071-1084, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21689595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21689595</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21689595[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.05.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21689595">Sopher et al. (2011)</a> found that CTCF downregulated ATXN7 (<a href="/entry/607640">607640</a>) expression by upregulating expression of SCAANT1 (ATXN7AS1; <a href="/entry/614481">614481</a>), a noncoding antisense regulatory transcript of ATXN7. They identified CTCF-binding sites flanking ATXN7 (<a href="/entry/607640">607640</a>) exon 3, which contains the translational start site and a CAG tract that causes spinocerebellar ataxia-7 (SCA7; <a href="/entry/164500">164500</a>) when expanded. <a href="#38" class="mim-tip-reference" title="Sopher, B. L., Ladd, P. D., Pineda, V. V., Libby, R. T., Sunkin, S. M., Hurley, J. B., Thienes, C. P., Gaasterland, T., Filippova, G. N., La Spada, A. R. <strong>CTCF regulates ataxin-7 expression through promotion of a convergently transcribed, antisense noncoding RNA.</strong> Neuron 70: 1071-1084, 2011.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21689595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21689595</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21689595[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.neuron.2011.05.027" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="21689595">Sopher et al. (2011)</a> generated transgenic mice expressing an approximately 13.5-kb human ATXN7 minigene construct containing SCAANT1, an alternative promoter (P2A) at the 3-prime end of ATXN7 intron 2, the ATXN7 translational start site in exon 3, a pathogenic CAG expansion in exon 3, and either wildtype or mutant CTCF-binding sites flanking exon 3. Transgenic mice with mutant CTCF-binding sites, but not those with wildtype CTCF-binding sites, showed reduced CTCF binding, elevated ATXN7 expression, and reduced SCAANT1 expression and developed features of SCA7. Reporter gene analysis using antisense ATXN7 constructs transfected in primary mouse cerebellar astrocytes showed that CTCF binding was required for maximal SCAANT1 promoter activity and that pathogenic CAG expansions reduced SCAANT1 promoter activity. Knockdown of CTCF in human retinoblastoma cells significantly reduced expression of SCAANT1 and increased ATXN7 mRNA expressed from the P2A promoter, but not from the canonical upstream promoter. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21689595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>The T-cell receptor (TCR)-alpha (TCRA; see <a href="/entry/186880">186880</a>)/TCR-delta (TCRD; see <a href="/entry/186810">186810</a>) locus contains both TCRA and TCRD gene segments that are regulated distinctly during thymocyte development. Using chromosome conformation capture, <a href="#36" class="mim-tip-reference" title="Shih, H.-Y., Verma-Gaur, J., Torkamani, A., Feeney, A. J., Galjart, N., Krangel, M. S. <strong>Tcra gene recombination is supported by a Tcra enhancer- and CTCF-dependent chromatin hub.</strong> Proc. Nat. Acad. Sci. 109: E3493-E3502, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23169622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23169622</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23169622[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1214131109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23169622">Shih et al. (2012)</a> demonstrated that the Tcra enhancer (E-alpha) region interacted directly with Tcra variable (TRAV; <a href="/entry/615442">615442</a>) and joining (TRAJ; <a href="/entry/615443">615443</a>) gene segments in Cd4 (<a href="/entry/186940">186940</a>)-positive/Cd8 (see <a href="/entry/186910">186910</a>)-positive double-positive (DP) mouse thymocytes. E-alpha promoted interactions between Trav and Traj segments, facilitating their synapsis. Ctcf bound to E-alpha and to many Tcra/Tcrd locus promoters, biased E-alpha to interact with these promoter elements, and was required for efficient Trav-Traj recombination. Loss of Ctcf in DP thymocytes dysregulated long-distance interactions among these elements, suppressed chromatin hub formation, and impaired initial Trav-Traj rearrangement. <a href="#36" class="mim-tip-reference" title="Shih, H.-Y., Verma-Gaur, J., Torkamani, A., Feeney, A. J., Galjart, N., Krangel, M. S. <strong>Tcra gene recombination is supported by a Tcra enhancer- and CTCF-dependent chromatin hub.</strong> Proc. Nat. Acad. Sci. 109: E3493-E3502, 2012. Note: Electronic Article.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23169622/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23169622</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23169622[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1073/pnas.1214131109" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23169622">Shih et al. (2012)</a> concluded that E-alpha and CTCF cooperate to create a developmentally regulated chromatin hub that supports TRAV-TRAJ synapsis and recombination. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23169622" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>By analyzing data from chromatin immunoprecipitation-sequencing and -microarray analyses in mouse embryonic stem cells, <a href="#14" class="mim-tip-reference" title="Gokhman, D., Livyatan, I., Sailaja, B. S., Melcer, S., Meshorer, E. <strong>Multilayered chromatin analysis reveals E2f, Smad and Zfx as transcriptional regulators of histones.</strong> Nature Struct. Molec. Biol. 20: 119-126, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23222641/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23222641</a>] [<a href="https://doi.org/10.1038/nsmb.2448" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23222641">Gokhman et al. (2013)</a> found that Ctcf repressed expression of core histones. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23222641" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#33" class="mim-tip-reference" title="Narendra, V., Rocha, P. P., An, D., Raviram, R., Skok, J. A., Mazzoni, E. O., Reinberg, D. <strong>CTCF establishes discrete functional chromatin domains at the Hox clusters during differentiation.</strong> Science 347: 1017-1021, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25722416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25722416</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25722416[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1262088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25722416">Narendra et al. (2015)</a> demonstrated that CTCF insulates adjacent yet antagonistic chromatin domains during embryonic stem cell differentiation into cervical motor neurons. Deletion of CTCF binding sites within the Hox clusters results in the expansion of active chromatin into the repressive domain. CTCF functions as an insulator by organizing Hox clusters into spatially disjoint domains. Ablation of CTCF binding disrupts topologic boundaries such that caudal Hox genes leave the repressed domain and become subject to transcriptional activation. Hence, <a href="#33" class="mim-tip-reference" title="Narendra, V., Rocha, P. P., An, D., Raviram, R., Skok, J. A., Mazzoni, E. O., Reinberg, D. <strong>CTCF establishes discrete functional chromatin domains at the Hox clusters during differentiation.</strong> Science 347: 1017-1021, 2015.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/25722416/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">25722416</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=25722416[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1126/science.1262088" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="25722416">Narendra et al. (2015)</a> concluded that CTCF is required to insulate facultative heterochromatin from impinging euchromatin to produce discrete positional identities. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=25722416" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Busslinger, G. A., Stocsits, R. R., van der Lelij, P., Axelsson, E., Tedeschi, A., Galjart, N., Peters, J.-M. <strong>Cohesin is positioned in mammalian genomes by transcription, CTCF and Wapl.</strong> Nature 544: 503-507, 2017.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28424523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28424523</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28424523[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature22063" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="28424523">Busslinger et al. (2017)</a> demonstrated that the distribution of cohesin in the mouse genome depends on transcription, Ctcf, and the cohesin release factor Wings apart-like (WAPL; <a href="/entry/610754">610754</a>). In Ctcf-depleted fibroblasts, cohesin cannot be properly recruited to Ctcf sites but instead accumulates at transcription start sites of active genes, where the cohesin-loading complex is located. In the absence of both Ctcf and Wapl, cohesin accumulates in up to 70-kilobase regions at 3-prime ends of active genes, in particular if these converge on each other. Changing gene expression modulates the position of these 'cohesin islands.' These findings indicated that transcription can relocate mammalian cohesin over long distances on DNA, as reported for yeast cohesin, that this translocation contributes to positioning cohesin at CTCF sites, and that active genes can be freed from cohesin either by transcription-mediated translocation or by WAPL-mediated release. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28424523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#7" class="mim-tip-reference" title="Chen, X., Ke, Y., Wu, K., Zhao, H., Sun, Y., Gao, L., Liu, Z., Zhang, J., Tao, W., Hou, Z., Liu, H., Liu, J., Chen, Z.-J. <strong>Key role for CTCF in establishing chromatin structure in human embryos.</strong> Nature 576: 306-310, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31801998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31801998</a>] [<a href="https://doi.org/10.1038/s41586-019-1812-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31801998">Chen et al. (2019)</a> reported that, unlike mouse sperm, human sperm cells do not express the chromatin regulator CTCF and their chromatin does not contain topologically associating domains (TADs). Following human fertilization, TAD structure is gradually established during embryonic development. In addition, A/B compartmentalization is lost in human embryos at the 2-cell stage and is reestablished during embryogenesis. Notably, blocking zygotic genome activation can inhibit TAD establishment in human embryos but not in mouse or Drosophila. Of note, CTCF is expressed at very low levels before zygotic genome activation, and is then highly expressed at the zygotic genome activation stage when TADs are observed. TAD organization is significantly reduced in CTCF knockdown embryos, suggesting that TAD establishment during zygotic genome activation in human embryos requires CTCF expression. <a href="#7" class="mim-tip-reference" title="Chen, X., Ke, Y., Wu, K., Zhao, H., Sun, Y., Gao, L., Liu, Z., Zhang, J., Tao, W., Hou, Z., Liu, H., Liu, J., Chen, Z.-J. <strong>Key role for CTCF in establishing chromatin structure in human embryos.</strong> Nature 576: 306-310, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31801998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31801998</a>] [<a href="https://doi.org/10.1038/s41586-019-1812-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31801998">Chen et al. (2019)</a> concluded that their results indicated that CTCF has a key role in the establishment of 3D chromatin structure during human embryogenesis. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31801998" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To elucidate the role of CTCF in cell-state transitions and cell proliferation, <a href="#40" class="mim-tip-reference" title="Stik, G., Vidal, E., Barrero, M., Cuartero, S., Vila-Casadesus, M., Mendieta-Esteban, J., Tian, T. V., Choi, J., Berenguer, C., Abad, A., Borsari, B., le Dily, F., Cramer, P., Marti-Renom, M. A., Stadhouders, R., Graf, T. <strong>CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response.</strong> Nature Genet. 52: 655-661, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32514124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32514124</a>] [<a href="https://doi.org/10.1038/s41588-020-0643-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32514124">Stik et al. (2020)</a> studied the effect of CTCF depletion during the conversion of human leukemic B cells into macrophages with minimal cell division. CTCF depletion disrupted TAD organization but not cell transdifferentiation. In contrast, CTCF depletion in induced macrophages impaired the full-blown upregulation of inflammatory genes after exposure to endotoxin. <a href="#40" class="mim-tip-reference" title="Stik, G., Vidal, E., Barrero, M., Cuartero, S., Vila-Casadesus, M., Mendieta-Esteban, J., Tian, T. V., Choi, J., Berenguer, C., Abad, A., Borsari, B., le Dily, F., Cramer, P., Marti-Renom, M. A., Stadhouders, R., Graf, T. <strong>CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response.</strong> Nature Genet. 52: 655-661, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32514124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32514124</a>] [<a href="https://doi.org/10.1038/s41588-020-0643-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32514124">Stik et al. (2020)</a> concluded that CTCF-dependent genome topology is not strictly required for a functional cell-fate conversion but facilitates a rapid and efficient response to an external stimulus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32514124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#2" class="mim-tip-reference" title="Ba, Z., Lou, J., Ye, A. Y., Dai, H.-Q., Dring, E. W., Lin, S. G., Jain, S., Kyritsis, N., Kieffer-Kwon, K.-R., Casellas, R., Alt, F. W. <strong>CTCF orchestrates long-range cohesin-driven V(D)J recombinational scanning.</strong> Nature 586: 305-310, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32717742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32717742</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32717742[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-020-2578-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32717742">Ba et al. (2020)</a> tested the potential of linear RAG (see <a href="/entry/179615">179615</a>) scanning to mediate distal V(H) usage in G1-arrested v-Abl pro-B cell lines, which undergo robust D-to-J(H) but little V(H)-to-DJ(H) rearrangements, presumably owing to lack of locus contraction. Through an auxin-inducible approach, <a href="#2" class="mim-tip-reference" title="Ba, Z., Lou, J., Ye, A. Y., Dai, H.-Q., Dring, E. W., Lin, S. G., Jain, S., Kyritsis, N., Kieffer-Kwon, K.-R., Casellas, R., Alt, F. W. <strong>CTCF orchestrates long-range cohesin-driven V(D)J recombinational scanning.</strong> Nature 586: 305-310, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32717742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32717742</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32717742[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-020-2578-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32717742">Ba et al. (2020)</a> degraded the cohesin component RAD21 (<a href="/entry/606462">606462</a>) or CTCF in these G1-arrested lines. Degradation of RAD21 eliminated all V(D)J recombination and interactions associated with RAG scanning, except for recombination center-located DQ52-to-J(H) joining, in which synapsis occurs by diffusion. Remarkably, while degradation of CTCF suppressed most CTCF looping factor-bound elements (CBE)-based chromatin interactions, it promoted robust recombination center interactions with, and robust V(H)-to-DJ(H) joining of, distal V(H)s, with patterns similar to those of locus-contracted primary pro-B cells. Thus, <a href="#2" class="mim-tip-reference" title="Ba, Z., Lou, J., Ye, A. Y., Dai, H.-Q., Dring, E. W., Lin, S. G., Jain, S., Kyritsis, N., Kieffer-Kwon, K.-R., Casellas, R., Alt, F. W. <strong>CTCF orchestrates long-range cohesin-driven V(D)J recombinational scanning.</strong> Nature 586: 305-310, 2020.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32717742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32717742</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32717742[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41586-020-2578-0" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="32717742">Ba et al. (2020)</a> concluded that downmodulation of CTCF-bound scanning-impediment activity promotes cohesin-driven RAG scanning across the 2.7-Mb Igh locus. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32717742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<p>In 3 boys with intellectual disability of varying severity, head circumference and/or body height either in the low normal range or below -2 standard deviations, and feeding difficulties (MRD21; <a href="/entry/615502">615502</a>), <a href="#15" class="mim-tip-reference" title="Gregor, A., Oti, M., Kouwenhoven, E. N., Hoyer, J., Sticht, H., Ekici, A. B., Kjaergaard, S., Rauch, A., Stunnenberg, H. G., Uebe, S., Vasileiou, G., Reis, A., Zhou, H., Zweier, C. <strong>De novo mutations in the genome organizer CTCF cause intellectual disability.</strong> Am. J. Hum. Genet. 93: 124-131, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23746550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23746550</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23746550[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23746550">Gregor et al. (2013)</a> identified de novo mutations in the CTCF gene (<a href="#0001">604167.0001</a>-<a href="#0003">604167.0003</a>). Whole-transcriptome sequencing of lymphocyte RNA from the 3 patients showed differential gene expression between patients and controls, with deregulation of genes involved in signal transduction; the gene expression patterns of the 2 patients with frameshift mutations were more similar to each other than to the more severely affected patient with the missense mutation, who had a more divergent profile. In a search of the Decipher database, <a href="#15" class="mim-tip-reference" title="Gregor, A., Oti, M., Kouwenhoven, E. N., Hoyer, J., Sticht, H., Ekici, A. B., Kjaergaard, S., Rauch, A., Stunnenberg, H. G., Uebe, S., Vasileiou, G., Reis, A., Zhou, H., Zweier, C. <strong>De novo mutations in the genome organizer CTCF cause intellectual disability.</strong> Am. J. Hum. Genet. 93: 124-131, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23746550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23746550</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23746550[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23746550">Gregor et al. (2013)</a> also identified a girl with intellectual disability who had a de novo deletion on chromosome 16 involving CTCF and 7 other genes. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23746550" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In 39 individuals with MRD21, <a href="#26" class="mim-tip-reference" title="Konrad, E. D. H., Nardini, N., Caliebe, A., Nagel, I., Young, D., Horvath, G., Santoro, S. L., Shuss, C., Ziegler, A., Bonneau, D., Kempers, M., Pfundt, R., and 52 others. <strong>CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum.</strong> Genet. Med. 21: 2723-2733, 2019.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31239556/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31239556</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=31239556[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/s41436-019-0585-z" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="31239556">Konrad et al. (2019)</a> identified mutations involving the CTCF gene, including 2 large deletions encompassing CTCF and neighboring genes, and 8 likely gene disruptive (2 frameshift and 6 nonsense), 2 splice site, and 20 missense mutations in CTCF. There were 2 familial cases and 6 cases in which one or both parents were unavailable for testing; the remaining cases were shown to be de novo. All missense variants involved highly conserved residues located in exons encoding one of the 11 zinc fingers. Among the missense variants, 7 amino acid residues were recurrently affected (R342, R368, H373, R377, P378, R448, R567). No genotype/phenotype correlations were identified. RNA sequencing on blood cells of 2 individuals with likely gene disruptive variants showed similarly decreased CTCF expression, and at least 2 of 3 individuals with missense variants had only mildly decreased CTCF levels, compared to healthy controls. The authors showed differential gene expression (sometimes upregulation and more often downregulation) for over 3,800 genes in affected persons, with enrichment for genes involved with neurodevelopmental disorders, compared to controls. There was significant overlap in the differentially expressed genes between individuals with likely gene disruptive variants and missense variants. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31239556" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs879255570 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255570;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs879255570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs879255570" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 9.5-year-old boy with mild intellectual disability, short stature, microcephaly, cleft palate, and congenital heart defects (MRD21; <a href="/entry/615502">615502</a>), <a href="#15" class="mim-tip-reference" title="Gregor, A., Oti, M., Kouwenhoven, E. N., Hoyer, J., Sticht, H., Ekici, A. B., Kjaergaard, S., Rauch, A., Stunnenberg, H. G., Uebe, S., Vasileiou, G., Reis, A., Zhou, H., Zweier, C. <strong>De novo mutations in the genome organizer CTCF cause intellectual disability.</strong> Am. J. Hum. Genet. 93: 124-131, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23746550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23746550</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23746550[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23746550">Gregor et al. (2013)</a> identified a de novo heterozygous 1-bp duplication (c.375dupT) in exon 3 of the CTCF gene, predicted to cause a frameshift resulting in a premature termination codon (Val126CysfsTer14). Analysis of patient lymphocytes revealed reduced expression of CTCF; sequencing confirmed the almost complete absence of the mutated allele, consistent with loss of function or haploinsufficiency. The duplication was not found in the parents, in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, in more than 1,500 in-house exomes, or in 820 healthy controls. The patient's heart defects consisted of atrial septal defect, patent ductus arteriosus, and mild aortic coarctation. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23746550" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs879255571 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255571;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs879255571" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs879255571" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<p>In a 9-year-old boy with borderline intelligence, microcephaly, developmental delay, pronounced learning difficulties, and behavioral problems (MRD21; <a href="/entry/615502">615502</a>), <a href="#15" class="mim-tip-reference" title="Gregor, A., Oti, M., Kouwenhoven, E. N., Hoyer, J., Sticht, H., Ekici, A. B., Kjaergaard, S., Rauch, A., Stunnenberg, H. G., Uebe, S., Vasileiou, G., Reis, A., Zhou, H., Zweier, C. <strong>De novo mutations in the genome organizer CTCF cause intellectual disability.</strong> Am. J. Hum. Genet. 93: 124-131, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23746550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23746550</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23746550[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23746550">Gregor et al. (2013)</a> identified a de novo 1-bp duplication (c.1186dupA) in exon 6 of the CTCF gene, predicted to cause a frameshift resulting in a premature termination codon. Analysis of patient lymphocytes revealed reduced expression of CTCF; sequencing confirmed the almost complete absence of the mutated allele, consistent with loss of function or haploinsufficiency. The duplication was not found in the parents, in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, in more than 1,500 in-house exomes, or in 820 healthy controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23746550" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<strong>.0003 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 21</strong>
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CTCF, ARG567TRP
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<div class="btn-group"> <button type="button" class="btn btn-default btn-xs dropdown-toggle mim-font" data-toggle="dropdown">rs879255516 <span class="caret"></span></button> <ul class="dropdown-menu"> <li><a href="https://www.ensembl.org/Homo_sapiens/Variation/Summary?v=rs879255516;toggle_HGVS_names=open" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'ensembl.org'})">Ensembl</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs879255516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'www.ncbi.nlm.nih.gov'})">NCBI</a></li> <li><a href="https://genome.ucsc.edu/cgi-bin/hgTracks?org=Human&db=hg38&clinvar=pack&omimAvSnp=pack&position=rs879255516" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'dbSNP', 'domain': 'genome.ucsc.edu'})">UCSC</a></li> </ul> </div>
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<a href="https://www.ncbi.nlm.nih.gov/clinvar?term=RCV000074335 OR RCV000413282 OR RCV002260512 OR RCV002399425 OR RCV004798770" target="_blank" class="btn btn-default btn-xs mim-tip-hint" title="RCV000074335, RCV000413282, RCV002260512, RCV002399425, RCV004798770" onclick="gtag('event', 'mim_outbound', {'name': 'ClinVar', 'domain': 'ncbi.nlm.nih.gov'})">RCV000074335...</a>
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<p>In a 4-year-old boy with severe intellectual disability with autistic features, microcephaly, and severe feeding difficulties (MRD21; <a href="/entry/615502">615502</a>), <a href="#15" class="mim-tip-reference" title="Gregor, A., Oti, M., Kouwenhoven, E. N., Hoyer, J., Sticht, H., Ekici, A. B., Kjaergaard, S., Rauch, A., Stunnenberg, H. G., Uebe, S., Vasileiou, G., Reis, A., Zhou, H., Zweier, C. <strong>De novo mutations in the genome organizer CTCF cause intellectual disability.</strong> Am. J. Hum. Genet. 93: 124-131, 2013.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/23746550/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">23746550</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=23746550[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1016/j.ajhg.2013.05.007" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="23746550">Gregor et al. (2013)</a> identified a de novo c.1699C-T transition (c.1699C-T, NM_006565.3) in the splice donor consensus site of exon 9 of the CTCF gene, resulting in an arg567-to-trp (R567W) substitution. The mutation was not found in the parents, in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, in more than 1,500 in-house exomes, or in 820 healthy controls. A second de novo synonymous variant, 1650C-T, was detected in the same exon on the same allele; in silico analysis showed no evidence for altered splicing, and analysis of patient lymphocytes showed CTCF expression levels similar to those of controls. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=23746550" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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<h4 href="#mimReferencesFold" id="mimReferencesToggle" class="mimTriangleToggle" style="cursor: pointer;" data-toggle="collapse">
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<span id="mimReferencesToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<strong>REFERENCES</strong>
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<a id="1" class="mim-anchor"></a>
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<a id="Akopov2006" class="mim-anchor"></a>
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<div class="">
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Akopov, S. B., Ruda, V. M., Batrak, V. V., Vetchinova, A. S., Chernov, I. P., Nikolaev, L. G., Bode, J., Sverdlov, E. D.
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<strong>Identification, genome mapping, and CTCF binding of potential insulators within the FXYD5-COX7A1 locus of human chromosome 19q13.12.</strong>
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Mammalian Genome 17: 1042-1049, 2006.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17019650/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17019650</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17019650" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1007/s00335-006-0037-3" target="_blank">Full Text</a>]
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<a id="Ba2020" class="mim-anchor"></a>
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Ba, Z., Lou, J., Ye, A. Y., Dai, H.-Q., Dring, E. W., Lin, S. G., Jain, S., Kyritsis, N., Kieffer-Kwon, K.-R., Casellas, R., Alt, F. W.
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<strong>CTCF orchestrates long-range cohesin-driven V(D)J recombinational scanning.</strong>
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Nature 586: 305-310, 2020.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32717742/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32717742</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=32717742[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32717742" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41586-020-2578-0" target="_blank">Full Text</a>]
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<a id="3" class="mim-anchor"></a>
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<a id="Bell2000" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Bell, A. C., Felsenfeld, G.
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<strong>Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene.</strong>
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Nature 405: 482-485, 2000.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10839546/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10839546</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10839546" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/35013100" target="_blank">Full Text</a>]
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<a id="4" class="mim-anchor"></a>
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<a id="Bell1999" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Bell, A. C., West, A. G., Felsenfeld, G.
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<strong>The protein CTCF is required for the enhancer blocking activity of vertebrate insulators.</strong>
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Cell 98: 387-396, 1999.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/10458613/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">10458613</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=10458613" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/s0092-8674(00)81967-4" target="_blank">Full Text</a>]
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<a id="Busslinger2017" class="mim-anchor"></a>
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Busslinger, G. A., Stocsits, R. R., van der Lelij, P., Axelsson, E., Tedeschi, A., Galjart, N., Peters, J.-M.
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<strong>Cohesin is positioned in mammalian genomes by transcription, CTCF and Wapl.</strong>
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Nature 544: 503-507, 2017.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/28424523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">28424523</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=28424523[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=28424523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature22063" target="_blank">Full Text</a>]
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<a id="Chao2002" class="mim-anchor"></a>
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Chao, W., Huynh, K. D., Spencer, R. J., Davidow, L. S., Lee, J. T.
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<strong>CTCF, a candidate trans-acting factor for X-inactivation choice.</strong>
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Science 295: 345-347, 2002.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11743158/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11743158</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11743158" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1065982" target="_blank">Full Text</a>]
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<a id="7" class="mim-anchor"></a>
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<a id="Chen2019" class="mim-anchor"></a>
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Chen, X., Ke, Y., Wu, K., Zhao, H., Sun, Y., Gao, L., Liu, Z., Zhang, J., Tao, W., Hou, Z., Liu, H., Liu, J., Chen, Z.-J.
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<strong>Key role for CTCF in establishing chromatin structure in human embryos.</strong>
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Nature 576: 306-310, 2019.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/31801998/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">31801998</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=31801998" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41586-019-1812-0" target="_blank">Full Text</a>]
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<a id="8" class="mim-anchor"></a>
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<a id="Donohoe2009" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Donohoe, M. E., Silva, S. S., Pinter, S. F., Xu, N., Lee, J. T.
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<strong>The pluripotency factor Oct4 interacts with Ctcf and also controls X-chromosome pairing and counting.</strong>
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Nature 460: 128-132, 2009.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/19536159/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">19536159</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=19536159[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=19536159" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature08098" target="_blank">Full Text</a>]
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<a id="Donohoe2007" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Donohoe, M. E., Zhang, L.-F., Xu, N., Shi, Y., Lee, J. T.
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<strong>Identification of a Ctcf cofactor, Yy1, for the X chromosome binary switch.</strong>
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Molec. Cell 25: 43-56, 2007.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/17218270/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">17218270</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=17218270" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.molcel.2006.11.017" target="_blank">Full Text</a>]
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<a id="Fedoriw2004" class="mim-anchor"></a>
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<div class="">
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Fedoriw, A. M., Stein, P., Svoboda, P., Schultz, R. M., Bartolomei, M. S.
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<strong>Transgenic RNAi reveals essential function for CTCF in H19 gene imprinting.</strong>
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Science 303: 238-240, 2004.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/14716017/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">14716017</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=14716017" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1126/science.1090934" target="_blank">Full Text</a>]
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<a id="Filippova1996" class="mim-anchor"></a>
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<div class="">
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Filippova, G. N., Fagerlie, S., Klenova, E. M., Myers, C., Dehner, Y., Goodwin, G., Neiman, P. E., Collins, S. J., Lobanenkov, V. V.
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<strong>An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/8649389/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">8649389</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=8649389" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1128/MCB.16.6.2802" target="_blank">Full Text</a>]
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<a id="Filippova1998" class="mim-anchor"></a>
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Filippova, G. N., Lindblom, A., Meincke, L. J., Klenova, E. M., Neiman, P. E., Collins, S. J., Doggett, N. A., Lobanenkov, V. V.
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<strong>A widely expressed transcription factor with multiple DNA sequence specificity, CTCF, is localized at chromosome segment 16q22.1 within one of the smallest regions of overlap for common deletions in breast and prostate cancers.</strong>
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Genes Chromosomes Cancer 22: 26-36, 1998.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/9591631/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">9591631</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=9591631" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<a id="Filippova2001" class="mim-anchor"></a>
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<div class="">
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/11479593/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">11479593</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=11479593" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng570" target="_blank">Full Text</a>]
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</p>
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[<a href="https://doi.org/10.1038/nsmb.2448" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.ajhg.2013.05.007" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature10495" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature08079" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng.857" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/35013106" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature07829" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/ddu344" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/j.molcel.2006.08.008" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1093/hmg/11.14.1627" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s1044-579x(02)00060-3" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/s41436-019-0585-z" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/s41586-019-1910-z" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1123191" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/190372a0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1084/jem.20071843" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1126/science.1262088" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1016/s0168-9525(01)02366-6" target="_blank">Full Text</a>]
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<strong>CTCF maintains differential methylation at the Igf2/H19 locus.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/12461525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">12461525</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=12461525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1057" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1073/pnas.1214131109" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21964334/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21964334</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21964334[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21964334" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature10442" target="_blank">Full Text</a>]
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<strong>CTCF regulates ataxin-7 expression through promotion of a convergently transcribed, antisense noncoding RNA.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/21689595/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">21689595</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=21689595[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=21689595" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1016/j.neuron.2011.05.027" target="_blank">Full Text</a>]
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<strong>CTCF mediates long-range chromatin looping and local histone modification in the beta-globin locus.</strong>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/16951251/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">16951251</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=16951251[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=16951251" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1101/gad.399506" target="_blank">Full Text</a>]
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/32514124/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">32514124</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=32514124" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/s41588-020-0643-0" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/nature06634" target="_blank">Full Text</a>]
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[<a href="https://doi.org/10.1038/ng.2007.5" target="_blank">Full Text</a>]
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Yu, W., Ginjala, V., Pant, V., Chernukhin, I., Whitehead, J., Docquier, F., Farrar, D., Tavoosidana, G., Mukhopadhyay, R., Kanduri, C., Oshimura, M., Feinberg, A. P., Lobanenkov, V., Klenova, E., Ohlsson, R.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/15361875/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">15361875</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=15361875" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/ng1426" target="_blank">Full Text</a>]
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Sonja A. Rasmussen - updated : 02/22/2023
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Ada Hamosh - updated : 12/23/2020<br>Ada Hamosh - updated : 08/31/2020<br>Ada Hamosh - updated : 08/28/2020<br>Ada Hamosh - updated : 03/24/2020<br>Ada Hamosh - updated : 04/02/2018<br>Ada Hamosh - updated : 2/1/2016<br>Patricia A. Hartz - updated : 1/16/2015<br>Patricia A. Hartz - updated : 11/25/2013<br>Paul J. Converse - updated : 11/6/2013<br>Marla J. F. O'Neill - updated : 10/28/2013<br>Paul J. Converse - updated : 9/18/2012<br>Patricia A. Hartz - updated : 2/10/2012<br>Ada Hamosh - updated : 11/29/2011<br>Ada Hamosh - updated : 11/21/2011<br>Patricia A. Hartz - updated : 8/10/2011<br>Patricia A. Hartz - updated : 9/17/2010<br>Ada Hamosh - updated : 8/25/2009<br>Paul J. Converse - updated : 8/13/2009<br>Ada Hamosh - updated : 5/19/2009<br>Ada Hamosh - updated : 3/7/2008<br>Victor A. McKusick - updated : 11/20/2007<br>Victor A. McKusick - updated : 2/27/2007<br>Patricia A. Hartz - updated : 2/9/2007<br>Patricia A. Hartz - updated : 11/6/2006<br>Patricia A. Hartz - updated : 10/5/2006<br>Ada Hamosh - updated : 5/26/2006<br>Victor A. McKusick - updated : 11/9/2004<br>Ada Hamosh - updated : 1/21/2004<br>George E. Tiller - updated : 5/30/2003<br>Victor A. McKusick - updated : 12/6/2002<br>Victor A. McKusick - updated : 11/15/2002<br>Paul J. Converse - updated : 6/6/2002<br>Ada Hamosh - updated : 1/17/2002<br>Ada Hamosh - updated : 7/26/2001<br>Ada Hamosh - updated : 5/24/2000
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Creation Date:
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Stylianos E. Antonarakis : 9/13/1999
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<a href="#mimCollapseEditHistory" role="button" data-toggle="collapse"> Edit History: </a>
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carol : 06/13/2024
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carol : 02/22/2023<br>alopez : 04/05/2022<br>alopez : 01/27/2021<br>alopez : 12/23/2020<br>alopez : 08/31/2020<br>carol : 08/29/2020<br>alopez : 08/28/2020<br>alopez : 03/24/2020<br>alopez : 04/02/2018<br>carol : 08/04/2016<br>carol : 02/02/2016<br>alopez : 2/1/2016<br>mgross : 1/20/2015<br>mcolton : 1/16/2015<br>mgross : 1/15/2015<br>mgross : 11/26/2013<br>mcolton : 11/25/2013<br>mcolton : 11/25/2013<br>mgross : 11/12/2013<br>mcolton : 11/7/2013<br>mcolton : 11/6/2013<br>carol : 10/28/2013<br>mgross : 9/18/2012<br>terry : 9/18/2012<br>terry : 8/31/2012<br>mgross : 2/15/2012<br>mgross : 2/14/2012<br>terry : 2/10/2012<br>alopez : 12/1/2011<br>terry : 11/29/2011<br>alopez : 11/29/2011<br>terry : 11/21/2011<br>mgross : 8/10/2011<br>terry : 8/10/2011<br>alopez : 9/17/2010<br>terry : 9/17/2010<br>alopez : 5/26/2010<br>terry : 5/25/2010<br>joanna : 11/23/2009<br>alopez : 8/27/2009<br>alopez : 8/27/2009<br>terry : 8/25/2009<br>mgross : 8/13/2009<br>terry : 8/13/2009<br>alopez : 6/4/2009<br>terry : 5/19/2009<br>wwang : 4/30/2008<br>terry : 4/29/2008<br>alopez : 3/20/2008<br>terry : 3/7/2008<br>alopez : 12/7/2007<br>terry : 11/20/2007<br>alopez : 3/22/2007<br>terry : 2/27/2007<br>mgross : 2/9/2007<br>wwang : 2/7/2007<br>mgross : 11/6/2006<br>mgross : 10/6/2006<br>terry : 10/5/2006<br>mgross : 8/15/2006<br>alopez : 6/1/2006<br>alopez : 5/31/2006<br>terry : 5/26/2006<br>tkritzer : 11/10/2004<br>terry : 11/9/2004<br>alopez : 1/22/2004<br>terry : 1/21/2004<br>cwells : 5/30/2003<br>alopez : 1/2/2003<br>alopez : 12/9/2002<br>terry : 12/6/2002<br>cwells : 11/18/2002<br>terry : 11/15/2002<br>mgross : 6/6/2002<br>alopez : 1/22/2002<br>terry : 1/17/2002<br>alopez : 7/31/2001<br>terry : 7/26/2001<br>carol : 10/24/2000<br>alopez : 5/24/2000<br>mgross : 9/13/1999
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<strong>*</strong> 604167
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CCCTC-BINDING FACTOR; CTCF
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<em>Alternative titles; symbols</em>
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TRANSCRIPTIONAL REPRESSOR CTCF
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<strong><em>HGNC Approved Gene Symbol: CTCF</em></strong>
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Cytogenetic location: 16q22.1
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Genomic coordinates <span class="small">(GRCh38)</span> : 16:67,562,526-67,639,185 </span>
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<span class="small">(from NCBI)</span>
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<strong>Gene-Phenotype Relationships</strong>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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16q22.1
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Intellectual developmental disorder, autosomal dominant 21
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<span class="mim-font">
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615502
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Autosomal dominant
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<span class="mim-font">
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3
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<strong>TEXT</strong>
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<strong>Description</strong>
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<p>Transcriptional insulators are DNA elements that set boundaries on the actions of enhancer and silencer elements and thereby organize the eukaryotic genome into regulatory domains (Kuhn and Geyer, 2003). All vertebrate insulators appear to use the versatile CTCF protein. CTCF uses various combinations of its 11 zinc fingers to recognize a variety of unrelated DNA sequences. Once bound to DNA, CTCF can function as a transcriptional insulator, repressor, or activator, depending on the context of the binding site (Jeong and Pfeifer, 2004). </p>
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<strong>Cloning and Expression</strong>
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<p>Filippova et al. (1996) isolated and analyzed human CTCF (CCCTC-binding factor) cDNA clones. They showed that the human CTCF protein contains 11 zinc finger domains and is exceptionally highly conserved, sharing 93% identity with the avian CTCF amino acid sequence. CTCF contains 2 transcription repressor domains transferable to a heterologous DNA-binding domain. Northern blot analysis revealed that the human CTCF gene was ubiquitously expressed as an approximately 4-kb transcript. </p><p>Ideraabdullah et al. (2014) stated that 7 CTCF protein isoforms migrate at apparent molecular masses ranging from 55 to 130 kD. CTCF can be posttranslationally modified in some tissues by phosphorylation, sumoylation, and poly(ADP-ribosyl)ation. It can also dimerize and multimerize with itself and interact with several protein partners as heterodimers. </p>
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<strong>Mapping</strong>
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<p>By FISH, Filippova et al. (1998) mapped the CTCF gene to chromosome 16q22.1 in a small region of overlap for common chromosomal deletions in sporadic breast and prostate tumors, suggesting that CTCF is a candidate tumor suppressor gene. </p>
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<strong>Biochemical Features</strong>
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<p><strong><em>Crystal Structure</em></strong></p><p>
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Li et al. (2020) showed that a segment within the CTCF N terminus interacts with the SA2 (300826)-SCC1 (600925) subunits of human cohesin. They reported a crystal structure of SA2-SCC1 in complex with CTCF at a resolution of 2.7 angstroms, which revealed the molecular basis of the interaction. Li et al. (2020) demonstrated that this interaction is specifically required for CTCF-anchored loops and contributes to the positioning of cohesin at CTCF binding sites. A similar motif is present in a number of established and newly identified cohesin ligands, including the cohesin release factor WAPL (610754). Li et al. (2020) concluded that their data suggested that CTCF enables the formation of chromatin loops by protecting cohesin against loop release. </p>
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<strong>Gene Function</strong>
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<p>Filippova et al. (1996) found that CTCF bound specifically to regulatory sequences in the promoter-proximal regions of chicken, mouse, and human MYC (190080) oncogenes. One CTCF-binding site, conserved in mouse and human MYC genes, was found immediately downstream of the major P2 promoter. Gel shift assays of nuclear extracts from mouse and human cells showed that CTCF was the predominant factor binding to this sequence. Mutation analysis of the P2-proximal CTCF-binding site and transient cotransfection experiments demonstrated that CTCF transcriptionally repressed the human MYC gene. Although there is 100% sequence identity in the DNA-binding domains of the avian and human CTCF proteins, the regulatory sequences recognized by CTCF in chicken and human MYC promoters were clearly diverged. Mutating the contact nucleotides confirmed that CTCF binding to the P2 promoter of the human MYC gene required a number of unique contact DNA bases that were absent in the CTCF-binding site of the chicken MYC gene. Moreover, proteolytic protection assays indicated that several more CTCF zinc fingers were involved in contacting the human CTCF-binding site than the chicken site. Gel shift assays utilizing successively deleted zinc finger domains indicated that CTCF zinc fingers 2 to 7 were involved in binding to the chicken MYC promoter, while fingers 3 to 11 mediated CTCF binding to the human promoter. This flexibility in zinc finger usage revealed CTCF to be a 'multivalent' transcription factor. </p><p>Bell et al. (1999) identified a 42-bp DNA fragment of the chicken beta-globin insulator that is both necessary and sufficient for enhancer-blocking activity in human cells. They showed that this sequence, FII, is the binding site for CTCF, and these CTCF-binding sites were present in all of the vertebrate enhancer-blocking elements examined. Bell et al. (1999) suggested that directional enhancer blocking by CTCF is a conserved component of gene regulation in vertebrates. </p><p>Bell and Felsenfeld (2000) and Hark et al. (2000) independently showed that CTCF binds to several sites within the unmethylated imprinted-control region (ICR1; 616186) between H19 (103280) and IGF2 (147470) that are essential for enhancer blocking. Hark et al. (2000) demonstrated that CTCF binding is abolished by DNA methylation of ICR1. Methylation of the CpGs within the CTCF binding sites eliminates binding of CTCF in vitro, and deletion of these sites results in loss of enhancer-blocking activity in vivo, thereby allowing gene expression. This CTCF-dependent enhancer-blocking element acts as an insulator. Bell and Felsenfeld (2000) suggested that it controls imprinting of IGF2 and that activity of this insulator is restricted to the maternal allele by specific DNA methylation of the paternal allele. Bell and Felsenfeld (2000) concluded that DNA methylation can control gene expression by modulating enhancer access to the gene promoter through regulation of an enhancer boundary. </p><p>An expansion of a CTG repeat at the DM1 locus causes myotonic dystrophy by altering the expression of 2 adjacent genes, DMPK (605377) and SIX5 (600963) and through a toxic effect of the repeat-containing RNA. Filippova et al. (2001) identified 2 CTCF binding sites that flank the CTG repeat and form an insulator element between DMPK and SIX5. Methylation of these sites prevents binding of CTCF, indicating that the DM1 locus methylation in congenital myotonic dystrophy would disrupt insulator function. Furthermore, CTCF binding sites are associated with CTG/CAG repeats at several other loci. Filippova et al. (2001) suggested a general role for CTG/CAG repeats as components of insulator elements at multiple sites in the human genome. </p><p>Chao et al. (2002) identified the insulator and transcription factor CTCF as a candidate trans-acting factor for X chromosome selection in mouse. The choice/imprinting center contains tandem CTCF binding sites that function in an enhancer-blocking assay. In vitro binding is reduced by CpG methylation and abolished by including non-CpG methylation. Chao et al. (2002) postulated that Tsix (300181) and CTCF together establish a regulatable epigenetic switch for X inactivation. Murine Tsix contains greater than 40 CTCF motifs, and the human sequence has greater than 10. </p><p>Two noncoding loci, TSIX and XIST (314670), regulate X chromosome inactivation by controlling homologous chromosome pairing, counting, and choice of chromosome to be inactivated. Donohoe et al. (2007) found that paired Ctcf-Yy1 (600013) elements are highly clustered within the counting/choice and imprinting domain of mouse Tsix, and they stated that similar clustering of paired YY1-CTCF sites occurs in the human X inactivation center. Immunoprecipitation and protein pull-down experiments showed direct binding between Ctcf and Yy1, and mutation analysis demonstrated that the highest affinity interactions occurred between the zinc finger of Yy1 and the N terminus of Ctcf. Donohoe et al. (2007) found that Yy1 +/- mouse embryonic stem cells had inappropriate Tsix downregulation and Xist upregulation, and knockdown of Ctcf through RNA interference yielded an identical phenotype. </p><p>Through combinatorial use of its 11 zinc fingers, CTCF binds to target sites of approximately 50 bp that have remarkable sequence variation. The formation of different CTCF-DNA complexes, some of which are methylation-sensitive, results in distinct functions, including gene activation, repression, silencing, and chromatin insulation. Disruption of the spectrum of target specificities by zinc finger mutations or by abnormal selective methylation of targets is associated with cancer. Ohlsson et al. (2001) stated that CTCF is a tumor suppressor gene. The role of CTCF in imprinting, however, suggested a functional richness not associated with other tumor suppressor genes. A crucial role for CTCF in natural selection was also suggested, because it relates to induction of functional and stable hemizygosity for expression of certain genes. </p><p>Normally, CTCF and the CTCF paralog BORIS (CTCFL; 607022) are expressed in a mutually exclusive pattern that correlates with resetting of methylation marks during male germ cell differentiation. The suggestion that BORIS directs epigenetic programming at CTCF target sites impinges on the observations that human BORIS is not only abnormally activated in a wide range of human cancers, but also maps to the cancer-associated amplification region at chromosome 20q13. Klenova et al. (2002) suggested that the rivalry occasioned by aberrant expression of BORIS in cancer may interfere with normal functions of CTCF, including growth repression, and contribute to epigenetic dysregulation, which is a common feature in human cancer. </p><p>Ishihara and Sasaki (2002) identified a binding site for CTCF in the intergenic region between H19 and L23mrp on mouse chromosome 7. This site is conserved between human and mouse, associated with a major DNase I-hypersensitive site, and bound by CTCF in vivo. Functional assays using reporter constructs demonstrated that this element may function as an insulator for the 3-prime boundary of this imprinted domain. The authors hypothesized that CTCF-dependent insulators may not only regulate but also delimit the imprinted domain. </p><p>Although the essential DNA methyltransferases had been discovered, proteins that regulate the sequence-specific establishment and maintenance of allelic methylation had not been identified. One candidate regulator of methylation was the zinc finger protein CTCF, which binds to the imprinting control region (ICR) of the genes IGF2 and H19. The unmethylated maternal ICR is a chromatin boundary that prevents distant enhancers from activating IGF2. In vitro experiments had suggested that CTCF mediates boundary activity of the maternal ICR, and that methylation of the paternal ICR abolishes this activity by preventing CTCF binding. Using mice with point mutations in all 4 CTCF sites in the ICR, Schoenherr et al. (2003) showed that maternally transmitted mutant ICRs in neonatal mice acquired a substantial but heterogeneous degree of methylation. Mutant ICRs in oocytes and blastocysts were not methylated, however, indicating that binding of CTCF is not required to establish the unmethylated ICR during oogenesis. The authors also showed that the mutant ICR lacked enhancer-blocking activity, as the expression of IGF2 is activated on mutant maternal chromosomes. Conversely, maternal H19 expression was reduced, suggesting a positive role for CTCF in the transcription of that gene. This was said to be the first in vivo demonstration of the multiple functions of CTCF in an ICR. </p><p>Fedoriw et al. (2004) used a transgenic RNA interference (RNAi)-based approach to generate oocytes with reduced amounts of CTCF protein, and found increased methylation of the H19 differentially methylated domain and decreased developmental competence of CTCF-deficient oocytes. Fedoriw et al. (2004) concluded that CTCF protects H19 differentially methylated domain from de novo methylation during oocyte growth and is required for normal preimplantation development. </p><p>Yu et al. (2004) identified poly(ADP-ribosyl)ation as a posttranslational mechanism for regulating CTCF insulator activity that adds to its versatility and its ability to effectively manage epigenetic programs. </p><p>Gene transcription may be regulated by remote enhancer or insulator regions through chromosome looping. Using a modification of chromosome conformation capture and fluorescence in situ hybridization, Ling et al. (2006) found that 1 allele of the Igf2/H19 ICR on mouse chromosome 7 colocalized with 1 allele of Wsb1 (610091)/Nf1 (613113) on mouse chromosome 11. Omission of Ctcf or deletion of the maternal ICR abrogated this association and altered Wsb1/Nf1 gene expression. Ling et al. (2006) concluded that their findings demonstrated that CTCF mediates an interchromosomal association, perhaps by directing distant DNA segments to a common transcription factory, and the data provided a model for long-range allele-specific associations between gene regions on different chromosomes that suggested a framework for DNA recombination and RNA trans-splicing. </p><p>Using embryonic mouse erythroid progenitor cells, Splinter et al. (2006) showed that Ctcf interacted with Ctcf-binding sites in the beta-globin locus (141900). Conditional deletion of Ctcf and targeted disruption of a DNA-binding site destabilized these long-range interactions and caused local loss of histone acetylation and gain of histone methylation, apparently without affecting transcription at the locus. </p><p>Using yeast 2-hybrid analysis and pull-down assays, Ishihara et al. (2006) found that the C-terminal region of mouse Chd8 (610528) interacted with the zinc finger domain of Ctcf. Chromatin immunoprecipitation analysis of a human hepatoma cell line revealed that CHD8 was present at CTCF target sites, such as the differentially methylated region of H19, the locus control region of beta-globin, and the promoter regions of the BRCA1 (113705) and MYC genes. Immunoprecipitation analysis demonstrated an endogenous complex of CHD8 and CTCF in HeLa cells. Knockdown of CHD8 in HeLa cells by RNA interference abolished the CTCF-dependent insulator activity of the H19 differentially methylated region, leading to reactivation of imprinted IGF2 from the maternal chromosome. Lack of CHD8 affected CpG methylation and histone acetylation around the CTCF-binding sites, which are adjacent to heterochromatin, of the BRCA1 and MYC genes. Ishihara et al. (2006) concluded that CTCF-CHD8 has a role in insulation and epigenetic regulation at active insulator sites. </p><p>Akopov et al. (2006) suggested an approach that allowed direct isolation of insulators by a simple positive-negative selection based on blocking enhancer effects by insulators. The approach allowed selection of fragments capable of blocking enhancers from mixtures of genomic fragments prepared from genomic regions of up to 1 Mb. Using this approach, a 1-Mb human genome locus was analyzed, the FXYD5 (606669)/COX7A1 (123995) locus on 19q13.13. The genes ATP4A (137216) and APLP1 (104775) within the locus studied were found to be flanked by insulators on both sides. Both genes are characterized by distinct tissue-specific expression that differs from the tissue specificity of the surrounding genes. The data were considered consistent with the concept that insulators subdivide genomic DNA into loop domains that comprise genes characterized by similar expression profiles. Using chromatin immunoprecipitation assay, Akopov et al. (2006) demonstrated also that at least 6 of the putative insulators revealed in this work could bind the CTCF transcription factor in vivo. They believed that the proposed approach could be a useful instrument for functional analysis of genomes. </p><p>X-chromosome inactivation ensures the equality of X-chromosome dosages in male and female mammals by silencing one X in the female (Lyon, 1961). To achieve the mutually exclusive designation of active X (Xa) and inactive X (Xi), the process necessitates that 2 Xs communicate in trans through homologous pairing. Pairing depends on a 15-kb region within the genes TSIX (300181) and XITE (300074). Xu et al. (2007) dissected the molecular requirements by transgenic methods in mouse cells and found that pairing can be recapitulated by a 1- to 2-kb subfragment of Tsix or Xite with little sequence similarity. However, a common denominator among them was the presence of the protein Ctcf, a chromatin insulator that they found to be essential for pairing. Pairing also depended on transcription. Transcriptional inhibition prevented new pair formation but did not perturb existing pairs. </p><p>Wendt et al. (2008) described cohesin-binding sites in the human genome and showed that most of these are associated with CTCF, a zinc finger protein required for transcriptional insulation. CTCF is dispensable for cohesin loading onto DNA, but is needed to enrich cohesin at specific binding sites. Cohesin enables CTCF to insulate promoters from distant enhancers and controls transcription at the H19/IGF2 locus. This role of cohesin seems to be independent of its role in cohesion. Wendt et al. (2008) proposed that cohesin functions as a transcriptional insulator, and speculated that subtle deficiencies in this function contribute to 'cohesinopathies' such as Cornelia de Lange syndrome (see 122470). </p><p>Majumder et al. (2008) found that small interfering RNA-mediated knockdown of CTCF, which binds XL9, an intergenic element between HLA-DRB1 (142857) and HLA-DQA1 (146880), reduced DRB1 and DQA1 expression. Coimmunoprecipitation experiments showed that CTCF, CIITA (MHC2TA; 600005), and RFX5 (601863) were in the same complex, suggesting that XL9 and the DRB1 and DQA1 proximal promoters may interact. Chromatin conformation capture (3C) analysis indicated that this was likely the case, and the 3C product was lost by knockdown of CTCF. RNA FISH analysis showed that both DRB1 and DQA1 could be expressed simultaneously in some cells. Majumder et al. (2008) concluded that CTCF interactions represent a novel mechanism for the regulation of these immune system major histocompatibility complex genes. </p><p>Heintzman et al. (2009) used a chromatin immunoprecipitation-based microarray method (ChIP-chip) to identify promoters, enhancers, and insulators in multiple cell types and investigate their roles in cell type-specific gene expression. They observed that the chromatin state at promoters and CTCF binding at insulators is largely invariant across diverse cell types. In contrast, enhancers are marked by highly cell type-specific histone modification patterns, strongly correlate to cell type-specific gene expression programs on a global scale, and are functionally active in a cell type-specific manner. Heintzman et al. (2009) concluded that their results defined over 55,000 potential transcriptional enhancers in the human genome, significantly expanding the current catalog of human enhancers and highlighting the role of these elements in cell type-specific gene expression. </p><p>Hadjur et al. (2009) showed that cohesin/CTCF formed the topologic and mechanistic basis for cell type-specific, long-range chromosomal interactions in cis at the developmentally regulated cytokine locus IFNG (147570) by associating with a select set of conserved sequence elements. </p><p>Donohoe et al. (2009) demonstrated that OCT4 (164177) lies at the top of the X chromosome inactivation (XCI) hierarchy and regulates XCI by triggering X chromosome pairing and counting. OCT4 directly binds TSIX (300181) and XITE (300074), 2 regulatory noncoding RNA genes of the X inactivation center, and also complexes with SCI transfactors CTCF and YY1 (600013) through protein-protein interactions. Depletion of Oct4 blocked homologous X-chromosome pairing and resulted in the inactivation of both X chromosomes in female mouse embryonic stem cells. Donohoe et al. (2009) concluded that they identified the first trans-factor that regulates counting, and ascribed new functions to OCT4 during X-chromosome reprogramming. </p><p>Using chromatin immunoprecipitation sequencing (ChIP-Seq), Kunarso et al. (2010) showed that genomic regions bound by CTCF were highly conserved between undifferentiated mouse and human embryonic stem cells. However, very little conservation was found for regions bound by OCT4 and NANOG (607937). Most of the differences in OCT4 and NANOG binding between species appeared to be due to species-specific insertion of transposable elements, such as endogenous ERV1 repeats, that generated unique OCT4- and NANOG-repeat-associated binding sites. </p><p>Handoko et al. (2011) characterized global Ctcf-associated chromatin organization in mouse embryonic stem cells and identified 1,480 intrachromosomal and 336 interchromosomal interactions with high confidence. Examination of histone methylation patterns, binding of RNA polymerase II (see 180660) or p300 enhancer (EP300; 602700), and nuclear lamina occupancy revealed 5 categories of intrachromosomal loops: loops with active characteristics, loops with repressive characteristics, loops functioning as hubs for enhancer and promoter activities, loops with opposite chromatin states flanking the boundaries, and loops lacking specific chromatin patterns. Loops of over 200 kb were more likely to be associated with active characteristics, while those of less than 200 kb were more likely to be silent. Lamin B (LMNB1; 150340)-associated loops appeared to act as insulators. Ctcf-mediated looping also brought the promoters of a number of genes into close contact (less than 10 kb) with p300 and enhanced gene expression. </p><p>Guo et al. (2011) reported in mice a key immunoglobulin heavy chain (Igh; see 147100) V(D)J recombination regulatory region, termed intergenic control region-1 (IGCR1), which lies between the V(H) and D clusters. Functionally, IGCR1 uses CTCF looping/insulator factor-binding elements and correspondingly mediates Igh loops containing distant enhancers. IGCR1 promotes normal B-cell development and balances antibody repertoires by inhibiting transcription and rearrangement of D(H)-proximal V(H) gene segments and promoting rearrangement of distal V(H) segments. IGCR1 maintains ordered and lineage-specific V(H)(D)J(H) recombination by suppressing V(H) joining to D segments not joined to J(H) segments, and V(H) to DJ(H) joins in thymocytes, respectively. IGCR1 is also required for feedback regulation and allelic exclusion of proximal V(H)-to-DJ(H) recombination. Guo et al. (2011) concluded that their studies elucidated a long-sought Igh V(D)J recombination control region and indicated a new role for the generally expressed CTCF protein. </p><p>Shukla et al. (2011) provided evidence that CTCF can promote inclusion of weak upstream exons by mediating local RNA polymerase II pausing both in a mammalian model system for alternative splicing, CD45 (151460), and genomewide. They further showed that CTCF binding to CD45 exon 5 is inhibited by DNA methylation, leading to reciprocal effects on exon 5 inclusion. Shukla et al. (2011) concluded that their results provided a mechanistic basis for developmental regulation of splicing outcome through heritable epigenetic marks. </p><p>Sopher et al. (2011) found that CTCF downregulated ATXN7 (607640) expression by upregulating expression of SCAANT1 (ATXN7AS1; 614481), a noncoding antisense regulatory transcript of ATXN7. They identified CTCF-binding sites flanking ATXN7 (607640) exon 3, which contains the translational start site and a CAG tract that causes spinocerebellar ataxia-7 (SCA7; 164500) when expanded. Sopher et al. (2011) generated transgenic mice expressing an approximately 13.5-kb human ATXN7 minigene construct containing SCAANT1, an alternative promoter (P2A) at the 3-prime end of ATXN7 intron 2, the ATXN7 translational start site in exon 3, a pathogenic CAG expansion in exon 3, and either wildtype or mutant CTCF-binding sites flanking exon 3. Transgenic mice with mutant CTCF-binding sites, but not those with wildtype CTCF-binding sites, showed reduced CTCF binding, elevated ATXN7 expression, and reduced SCAANT1 expression and developed features of SCA7. Reporter gene analysis using antisense ATXN7 constructs transfected in primary mouse cerebellar astrocytes showed that CTCF binding was required for maximal SCAANT1 promoter activity and that pathogenic CAG expansions reduced SCAANT1 promoter activity. Knockdown of CTCF in human retinoblastoma cells significantly reduced expression of SCAANT1 and increased ATXN7 mRNA expressed from the P2A promoter, but not from the canonical upstream promoter. </p><p>The T-cell receptor (TCR)-alpha (TCRA; see 186880)/TCR-delta (TCRD; see 186810) locus contains both TCRA and TCRD gene segments that are regulated distinctly during thymocyte development. Using chromosome conformation capture, Shih et al. (2012) demonstrated that the Tcra enhancer (E-alpha) region interacted directly with Tcra variable (TRAV; 615442) and joining (TRAJ; 615443) gene segments in Cd4 (186940)-positive/Cd8 (see 186910)-positive double-positive (DP) mouse thymocytes. E-alpha promoted interactions between Trav and Traj segments, facilitating their synapsis. Ctcf bound to E-alpha and to many Tcra/Tcrd locus promoters, biased E-alpha to interact with these promoter elements, and was required for efficient Trav-Traj recombination. Loss of Ctcf in DP thymocytes dysregulated long-distance interactions among these elements, suppressed chromatin hub formation, and impaired initial Trav-Traj rearrangement. Shih et al. (2012) concluded that E-alpha and CTCF cooperate to create a developmentally regulated chromatin hub that supports TRAV-TRAJ synapsis and recombination. </p><p>By analyzing data from chromatin immunoprecipitation-sequencing and -microarray analyses in mouse embryonic stem cells, Gokhman et al. (2013) found that Ctcf repressed expression of core histones. </p><p>Narendra et al. (2015) demonstrated that CTCF insulates adjacent yet antagonistic chromatin domains during embryonic stem cell differentiation into cervical motor neurons. Deletion of CTCF binding sites within the Hox clusters results in the expansion of active chromatin into the repressive domain. CTCF functions as an insulator by organizing Hox clusters into spatially disjoint domains. Ablation of CTCF binding disrupts topologic boundaries such that caudal Hox genes leave the repressed domain and become subject to transcriptional activation. Hence, Narendra et al. (2015) concluded that CTCF is required to insulate facultative heterochromatin from impinging euchromatin to produce discrete positional identities. </p><p>Busslinger et al. (2017) demonstrated that the distribution of cohesin in the mouse genome depends on transcription, Ctcf, and the cohesin release factor Wings apart-like (WAPL; 610754). In Ctcf-depleted fibroblasts, cohesin cannot be properly recruited to Ctcf sites but instead accumulates at transcription start sites of active genes, where the cohesin-loading complex is located. In the absence of both Ctcf and Wapl, cohesin accumulates in up to 70-kilobase regions at 3-prime ends of active genes, in particular if these converge on each other. Changing gene expression modulates the position of these 'cohesin islands.' These findings indicated that transcription can relocate mammalian cohesin over long distances on DNA, as reported for yeast cohesin, that this translocation contributes to positioning cohesin at CTCF sites, and that active genes can be freed from cohesin either by transcription-mediated translocation or by WAPL-mediated release. </p><p>Chen et al. (2019) reported that, unlike mouse sperm, human sperm cells do not express the chromatin regulator CTCF and their chromatin does not contain topologically associating domains (TADs). Following human fertilization, TAD structure is gradually established during embryonic development. In addition, A/B compartmentalization is lost in human embryos at the 2-cell stage and is reestablished during embryogenesis. Notably, blocking zygotic genome activation can inhibit TAD establishment in human embryos but not in mouse or Drosophila. Of note, CTCF is expressed at very low levels before zygotic genome activation, and is then highly expressed at the zygotic genome activation stage when TADs are observed. TAD organization is significantly reduced in CTCF knockdown embryos, suggesting that TAD establishment during zygotic genome activation in human embryos requires CTCF expression. Chen et al. (2019) concluded that their results indicated that CTCF has a key role in the establishment of 3D chromatin structure during human embryogenesis. </p><p>To elucidate the role of CTCF in cell-state transitions and cell proliferation, Stik et al. (2020) studied the effect of CTCF depletion during the conversion of human leukemic B cells into macrophages with minimal cell division. CTCF depletion disrupted TAD organization but not cell transdifferentiation. In contrast, CTCF depletion in induced macrophages impaired the full-blown upregulation of inflammatory genes after exposure to endotoxin. Stik et al. (2020) concluded that CTCF-dependent genome topology is not strictly required for a functional cell-fate conversion but facilitates a rapid and efficient response to an external stimulus. </p><p>Ba et al. (2020) tested the potential of linear RAG (see 179615) scanning to mediate distal V(H) usage in G1-arrested v-Abl pro-B cell lines, which undergo robust D-to-J(H) but little V(H)-to-DJ(H) rearrangements, presumably owing to lack of locus contraction. Through an auxin-inducible approach, Ba et al. (2020) degraded the cohesin component RAD21 (606462) or CTCF in these G1-arrested lines. Degradation of RAD21 eliminated all V(D)J recombination and interactions associated with RAG scanning, except for recombination center-located DQ52-to-J(H) joining, in which synapsis occurs by diffusion. Remarkably, while degradation of CTCF suppressed most CTCF looping factor-bound elements (CBE)-based chromatin interactions, it promoted robust recombination center interactions with, and robust V(H)-to-DJ(H) joining of, distal V(H)s, with patterns similar to those of locus-contracted primary pro-B cells. Thus, Ba et al. (2020) concluded that downmodulation of CTCF-bound scanning-impediment activity promotes cohesin-driven RAG scanning across the 2.7-Mb Igh locus. </p>
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<strong>Molecular Genetics</strong>
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<p>In 3 boys with intellectual disability of varying severity, head circumference and/or body height either in the low normal range or below -2 standard deviations, and feeding difficulties (MRD21; 615502), Gregor et al. (2013) identified de novo mutations in the CTCF gene (604167.0001-604167.0003). Whole-transcriptome sequencing of lymphocyte RNA from the 3 patients showed differential gene expression between patients and controls, with deregulation of genes involved in signal transduction; the gene expression patterns of the 2 patients with frameshift mutations were more similar to each other than to the more severely affected patient with the missense mutation, who had a more divergent profile. In a search of the Decipher database, Gregor et al. (2013) also identified a girl with intellectual disability who had a de novo deletion on chromosome 16 involving CTCF and 7 other genes. </p><p>In 39 individuals with MRD21, Konrad et al. (2019) identified mutations involving the CTCF gene, including 2 large deletions encompassing CTCF and neighboring genes, and 8 likely gene disruptive (2 frameshift and 6 nonsense), 2 splice site, and 20 missense mutations in CTCF. There were 2 familial cases and 6 cases in which one or both parents were unavailable for testing; the remaining cases were shown to be de novo. All missense variants involved highly conserved residues located in exons encoding one of the 11 zinc fingers. Among the missense variants, 7 amino acid residues were recurrently affected (R342, R368, H373, R377, P378, R448, R567). No genotype/phenotype correlations were identified. RNA sequencing on blood cells of 2 individuals with likely gene disruptive variants showed similarly decreased CTCF expression, and at least 2 of 3 individuals with missense variants had only mildly decreased CTCF levels, compared to healthy controls. The authors showed differential gene expression (sometimes upregulation and more often downregulation) for over 3,800 genes in affected persons, with enrichment for genes involved with neurodevelopmental disorders, compared to controls. There was significant overlap in the differentially expressed genes between individuals with likely gene disruptive variants and missense variants. </p>
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<strong>ALLELIC VARIANTS</strong>
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<strong>3 Selected Examples):</strong>
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<strong>.0001 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 21</strong>
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CTCF, 1-BP DUP, 375T
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SNP: rs879255570,
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ClinVar: RCV000074333
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<p>In a 9.5-year-old boy with mild intellectual disability, short stature, microcephaly, cleft palate, and congenital heart defects (MRD21; 615502), Gregor et al. (2013) identified a de novo heterozygous 1-bp duplication (c.375dupT) in exon 3 of the CTCF gene, predicted to cause a frameshift resulting in a premature termination codon (Val126CysfsTer14). Analysis of patient lymphocytes revealed reduced expression of CTCF; sequencing confirmed the almost complete absence of the mutated allele, consistent with loss of function or haploinsufficiency. The duplication was not found in the parents, in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, in more than 1,500 in-house exomes, or in 820 healthy controls. The patient's heart defects consisted of atrial septal defect, patent ductus arteriosus, and mild aortic coarctation. </p>
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<strong>.0002 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 21</strong>
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CTCF, 1-BP DUP, 1186A
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SNP: rs879255571,
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ClinVar: RCV000074334
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<p>In a 9-year-old boy with borderline intelligence, microcephaly, developmental delay, pronounced learning difficulties, and behavioral problems (MRD21; 615502), Gregor et al. (2013) identified a de novo 1-bp duplication (c.1186dupA) in exon 6 of the CTCF gene, predicted to cause a frameshift resulting in a premature termination codon. Analysis of patient lymphocytes revealed reduced expression of CTCF; sequencing confirmed the almost complete absence of the mutated allele, consistent with loss of function or haploinsufficiency. The duplication was not found in the parents, in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, in more than 1,500 in-house exomes, or in 820 healthy controls. </p>
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<span class="mim-font">
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<strong>.0003 INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 21</strong>
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CTCF, ARG567TRP
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SNP: rs879255516,
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ClinVar: RCV000074335, RCV000413282, RCV002260512, RCV002399425, RCV004798770
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<span class="mim-text-font">
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<p>In a 4-year-old boy with severe intellectual disability with autistic features, microcephaly, and severe feeding difficulties (MRD21; 615502), Gregor et al. (2013) identified a de novo c.1699C-T transition (c.1699C-T, NM_006565.3) in the splice donor consensus site of exon 9 of the CTCF gene, resulting in an arg567-to-trp (R567W) substitution. The mutation was not found in the parents, in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases, in more than 1,500 in-house exomes, or in 820 healthy controls. A second de novo synonymous variant, 1650C-T, was detected in the same exon on the same allele; in silico analysis showed no evidence for altered splicing, and analysis of patient lymphocytes showed CTCF expression levels similar to those of controls. </p>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<p />
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<ol>
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Akopov, S. B., Ruda, V. M., Batrak, V. V., Vetchinova, A. S., Chernov, I. P., Nikolaev, L. G., Bode, J., Sverdlov, E. D.
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<strong>Identification, genome mapping, and CTCF binding of potential insulators within the FXYD5-COX7A1 locus of human chromosome 19q13.12.</strong>
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Mammalian Genome 17: 1042-1049, 2006.
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[PubMed: 17019650]
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[Full Text: https://doi.org/10.1007/s00335-006-0037-3]
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</p>
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Ba, Z., Lou, J., Ye, A. Y., Dai, H.-Q., Dring, E. W., Lin, S. G., Jain, S., Kyritsis, N., Kieffer-Kwon, K.-R., Casellas, R., Alt, F. W.
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<strong>CTCF orchestrates long-range cohesin-driven V(D)J recombinational scanning.</strong>
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Nature 586: 305-310, 2020.
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[PubMed: 32717742]
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[Full Text: https://doi.org/10.1038/s41586-020-2578-0]
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</p>
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</li>
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<li>
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<p class="mim-text-font">
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Bell, A. C., Felsenfeld, G.
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<strong>Methylation of a CTCF-dependent boundary controls imprinted expression of the Igf2 gene.</strong>
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Nature 405: 482-485, 2000.
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[PubMed: 10839546]
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Shukla, S., Kavak, E., Gregory, M., Imashimizu, M., Shutinoski, B., Kashlev, M., Oberdoerffer, P., Sandberg, R., Oberdoerffer, S.
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<strong>CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing.</strong>
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Nature 479: 74-79, 2011.
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[PubMed: 21964334]
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[Full Text: https://doi.org/10.1038/nature10442]
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Sopher, B. L., Ladd, P. D., Pineda, V. V., Libby, R. T., Sunkin, S. M., Hurley, J. B., Thienes, C. P., Gaasterland, T., Filippova, G. N., La Spada, A. R.
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<strong>CTCF regulates ataxin-7 expression through promotion of a convergently transcribed, antisense noncoding RNA.</strong>
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Neuron 70: 1071-1084, 2011.
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[PubMed: 21689595]
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[Full Text: https://doi.org/10.1016/j.neuron.2011.05.027]
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Splinter, E., Heath, H., Kooren, J., Palstra, R.-J., Klous, P., Grosveld, F., Galjart, N., de Laat, W.
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<strong>CTCF mediates long-range chromatin looping and local histone modification in the beta-globin locus.</strong>
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Genes Dev. 20: 2349-2354, 2006.
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[PubMed: 16951251]
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Stik, G., Vidal, E., Barrero, M., Cuartero, S., Vila-Casadesus, M., Mendieta-Esteban, J., Tian, T. V., Choi, J., Berenguer, C., Abad, A., Borsari, B., le Dily, F., Cramer, P., Marti-Renom, M. A., Stadhouders, R., Graf, T.
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<strong>CTCF is dispensable for immune cell transdifferentiation but facilitates an acute inflammatory response.</strong>
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Nature Genet. 52: 655-661, 2020.
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[PubMed: 32514124]
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[Full Text: https://doi.org/10.1038/s41588-020-0643-0]
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Wendt, K. S., Yoshida, K., Itoh, T., Bando, M., Koch, B., Schirghuber, E., Tsutsumi, S., Nagae, G., Ishihara, K., Mishiro, T., Yahata, K., Imamoto, F., Aburatani, H., Nakao, M., Imamoto, N., Maeshima, K., Shirahige, K., Peters, J.-M.
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<strong>Cohesin mediates transcriptional insulation by CCCTC-binding factor.</strong>
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Nature 451: 796-801, 2008.
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Xu, N., Donohoe, M. E., Silva, S. S., Lee, J. T.
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<strong>Evidence that homologous X-chromosome pairing requires transcription and Ctcf protein.</strong>
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Nature Genet. 39: 1390-1396, 2007.
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[PubMed: 17952071]
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[Full Text: https://doi.org/10.1038/ng.2007.5]
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Yu, W., Ginjala, V., Pant, V., Chernukhin, I., Whitehead, J., Docquier, F., Farrar, D., Tavoosidana, G., Mukhopadhyay, R., Kanduri, C., Oshimura, M., Feinberg, A. P., Lobanenkov, V., Klenova, E., Ohlsson, R.
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<strong>Poly(ADP-ribosyl)ation regulates CTCF-dependent chromatin insulation.</strong>
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Nature Genet. 36: 1105-1110, 2004.
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[PubMed: 15361875]
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[Full Text: https://doi.org/10.1038/ng1426]
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Sonja A. Rasmussen - updated : 02/22/2023<br>Ada Hamosh - updated : 12/23/2020<br>Ada Hamosh - updated : 08/31/2020<br>Ada Hamosh - updated : 08/28/2020<br>Ada Hamosh - updated : 03/24/2020<br>Ada Hamosh - updated : 04/02/2018<br>Ada Hamosh - updated : 2/1/2016<br>Patricia A. Hartz - updated : 1/16/2015<br>Patricia A. Hartz - updated : 11/25/2013<br>Paul J. Converse - updated : 11/6/2013<br>Marla J. F. O'Neill - updated : 10/28/2013<br>Paul J. Converse - updated : 9/18/2012<br>Patricia A. Hartz - updated : 2/10/2012<br>Ada Hamosh - updated : 11/29/2011<br>Ada Hamosh - updated : 11/21/2011<br>Patricia A. Hartz - updated : 8/10/2011<br>Patricia A. Hartz - updated : 9/17/2010<br>Ada Hamosh - updated : 8/25/2009<br>Paul J. Converse - updated : 8/13/2009<br>Ada Hamosh - updated : 5/19/2009<br>Ada Hamosh - updated : 3/7/2008<br>Victor A. McKusick - updated : 11/20/2007<br>Victor A. McKusick - updated : 2/27/2007<br>Patricia A. Hartz - updated : 2/9/2007<br>Patricia A. Hartz - updated : 11/6/2006<br>Patricia A. Hartz - updated : 10/5/2006<br>Ada Hamosh - updated : 5/26/2006<br>Victor A. McKusick - updated : 11/9/2004<br>Ada Hamosh - updated : 1/21/2004<br>George E. Tiller - updated : 5/30/2003<br>Victor A. McKusick - updated : 12/6/2002<br>Victor A. McKusick - updated : 11/15/2002<br>Paul J. Converse - updated : 6/6/2002<br>Ada Hamosh - updated : 1/17/2002<br>Ada Hamosh - updated : 7/26/2001<br>Ada Hamosh - updated : 5/24/2000
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