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<article><div class="banner banner--gray banner--compact" style="--banner-background-image: url('/sites/default/files/media/image/2021-03/2015.jpg');--banner-background-focus: 50% 50%"><div class="banner__wrapper"><div class="banner__container"><h2 class="banner__heading">NIH Research Festival</h2><div class="banner__content"><p><strong><time datetime="2015-09-16">September 16</time> – <time datetime="2015-09-18">18, 2015</time></strong></p></div></div></div></div></article>
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<div class="section"><div data-drupal-messages-fallback class="hidden"></div></div><main role="main"><div id="main-content" tabindex="-1"></div><div class="section"><div class="content-sidebar"><div class="content-sidebar__main"><div class="content-sidebar__main-content"><div id="block-mainpagecontent-2"><article><h1>Enhancer regulation by H3K4me1/2 methyltransferase MLL4</h1><div class="schedule"><div class="schedule__label"><div class="schedule__label-text"><time datetime="2015-09-18">Friday, September 18, 2015</time>
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– Poster Session V
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</div></div><div class="schedule__content"><div class="schedule__item"><div class="schedule__time">2:00 – 3:30 p.m.</div><div class="schedule__description"><p><strong>FAES Terrace</strong></p></div><div class="schedule__description"><p><strong>NIDDK</strong></p></div><div class="schedule__description"><p><strong>CHROM-2</strong></p></div></div></div></div><h2>Authors</h2><ul><li>JE Lee</li><li>C Wang</li><li>W Peng</li><li>K Ge</li></ul><h2>Abstract</h2><p>Enhancers play a central role in cell-type-specific gene expression and are marked by H3K4me1/2. Active enhancers are further marked by H3K27ac. However, the methyltransferases responsible for H3K4me1/2 on enhancers remain elusive. Furthermore, how these enzymes function on enhancers is unclear. Here we identify MLL4 as a major H3K4 mono- and di-methyltransferase with partial functional redundancy with MLL3. Using adipogenesis and myogenesis as model systems, we show that MLL4 exhibits cell-type- and differentiation-stage-specific genomic binding and is predominantly localized on enhancers. MLL4 co-localizes with lineage-determining TFs on active enhancers during differentiation. Deletion of MLL4 markedly decreases H3K4me1/2, H3K27ac, and PolII levels on enhancers and leads to severe defects in differentiation. Together, these findings identify MLL4 as a major H3K4 mono- and di-methyltransferase essential for enhancer activation during cell differentiation. Our data suggest a step-wise model of enhancer activation. Step 1, pioneer TFs bind enhancer-like regions. Step 2, enhancer commissioning by MLL4. Pioneer TFs cooperatively recruit MLL4 to perform H3K4me1/2 on enhancer-like regions. Step 3, enhancer activation by H3K27 acetyltransferases CBP/p300, followed by PolII recruitment, establishment of enhancer–promoter interaction, and activation of cell-type-specific gene expression. Our unpublished data in embryonic stem cells show that MLL4 co-localizes with core circuitry TFs Oct4, Sox2 and Nanog on active ESC enhancers. Interestingly, MLL4 is dispensable for ESC self-renewal, likely due to the functional redundancy with other H3K4me1/2 methyltransferases. However, by regulating de novo enhancer activation, MLL4 is essential not only for ESC differentiation but also for somatic cell reprogramming into ESC-like iPS cells.</p><p><strong>Scientific Focus Area</strong>: Chromosome Biology</p><p class="updated"><small>This page was last updated on Friday, March 26, 2021</small></p></article>
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