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Review
. 2021 Aug 20;49(14):7825-7838.
doi: 10.1093/nar/gkab520.

CTCF as a regulator of alternative splicing: new tricks for an old player

Adel B Alharbi  1   2   3   4   5 , Ulf Schmitz  1   3   4 , Charles G Bailey  1   4   5 , John E J Rasko  1   4   6
Affiliations
Review

CTCF as a regulator of alternative splicing: new tricks for an old player

Adel B Alharbi et al. Nucleic Acids Res. .

Abstract

Three decades of research have established the CCCTC-binding factor (CTCF) as a ubiquitously expressed chromatin organizing factor and master regulator of gene expression. A new role for CTCF as a regulator of alternative splicing (AS) has now emerged. CTCF has been directly and indirectly linked to the modulation of AS at the individual transcript and at the transcriptome-wide level. The emerging role of CTCF-mediated regulation of AS involves diverse mechanisms; including transcriptional elongation, DNA methylation, chromatin architecture, histone modifications, and regulation of splicing factor expression and assembly. CTCF thereby appears to not only co-ordinate gene expression regulation but contributes to the modulation of transcriptomic complexity. In this review, we highlight previous discoveries regarding the role of CTCF in AS. In addition, we summarize detailed mechanisms by which CTCF mediates AS regulation. We propose opportunities for further research designed to examine the possible fate of CTCF-mediated alternatively spliced genes and associated biological consequences. CTCF has been widely acknowledged as the 'master weaver of the genome'. Given its multiple connections, further characterization of CTCF's emerging role in splicing regulation might extend its functional repertoire towards a 'conductor of the splicing orchestra'.

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Figures

Figure 1.
Figure 1.
Mechanisms of CTCF-mediated regulation of alternative splicing. CTCF has been linked to key determinants of AS regulation which can be broadly categorized into co-transcriptional, genomic and epigenetic mechanisms. During co-transcriptional regulation, CTCF-mediated AS is regulated by stalling RNAPII transcriptional elongation (33–35,42), controlling DNA methylation (60–62) and recruitment of splicing factors (42,58,66). While the co-transcriptional factors have been mostly experimentally verified, the genomic and epigenetic regulatory roles of CTCF in modulating AS are putative. These involve localization of CTCF binding sites proximal to splice sites (33–38,40–42,44), chromatin architecture (35,36), nucleosome enrichment (7,85–87), histone modification (35,46) and regulation of CTCF binding via DNA methylation patterns (33,34,36,38,40,41).
Figure 2.
Figure 2.
CTCF-mediated co-transcriptional regulation of alternative splicing. Schematic representation of co-transcriptional mechanisms by which CTCF modulates AS. (A) The ‘roadblock’ mechanism involves altering RNAPII elongation rate in a methylation-dependent manner (33,34). (B) CTCF regulation of DNA methylation via activation of PARP1 and PARylation (60,61), which are also involved in other AS-related regulatory activities (66–69). (C) Splicing factor recruitment might also take part in CTCF-mediated AS regulation through direct interaction with RNA binding proteins (42,58,70) or other transcription factors involved in AS such as PARP1 (66), MeCP2 (38), YB-1 (108,109) and HP1α (46,124,127). SF3B1 and SRSF3 are examples of RNA-binding proteins.
Figure 3.
Figure 3.
CTCF-mediated genomic and epigenetic regulation of alternative splicing. Schematic representation of putative genomic roles for CTCF in AS. (A) Formation of chromatin loops to bring alternatively spliced exons into physical proximity of the gene promoter (44). (B) Nucleosome occupancy-mediated altering of RNAPII elongation rate. (C) DNA methylation differentially regulates AS by CTCF and MeCP2. Unmethylated CpGs within CTCF sites promote exon inclusion via CTCF binding while DNA methylation favors exon inclusion via MeCP2 binding (38).
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References

    1. Lobanenkov V.V., Nicolas R.H., Adler V.V., Paterson H., Klenova E.M., Polotskaja A.V., Goodwin G.H.. A novel sequence-specific DNA binding protein which interacts with three regularly spaced direct repeats of the CCCTC-motif in the 5′-flanking sequence of the chicken c-myc gene. Oncogene. 1990; 5:1743–1753. - PubMed
    1. Klenova E.M., Nicolas R.H., Paterson H.F., Carne A.F., Heath C.M., Goodwin G.H., Neiman P.E., Lobanenkov V.V.. CTCF, a conserved nuclear factor required for optimal transcriptional activity of the chicken c-myc gene, is an 11-Zn-finger protein differentially expressed in multiple forms. Mol. Cell. Biol. 1993; 13:7612–7624. - PMC - PubMed
    1. Bell A.C., West A.G., Felsenfeld G.. The protein CTCF is required for the enhancer blocking activity of vertebrate insulators. Cell. 1999; 98:387–396. - PubMed
    1. Filippova G.N., Fagerlie S., Klenova E.M., Myers C., Dehner Y., Goodwin G., Neiman P.E., Collins S.J., Lobanenkov V.V.. An exceptionally conserved transcriptional repressor, CTCF, employs different combinations of zinc fingers to bind diverged promoter sequences of avian and mammalian c-myc oncogenes. Mol. Cell. Biol. 1996; 16:2802–2813. - PMC - PubMed
    1. Ohlsson R., Renkawitz R., Lobanenkov V.. CTCF is a uniquely versatile transcription regulator linked to epigenetics and disease. Trends Genet. 2001; 17:520–527. - PubMed

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