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’.
Highlights
CTCF – an old playerCCCTC-binding factor (CTCF) was first identified as a nuclear DNA-binding protein, which negatively regulates chicken c-myc expression by interacting with three regularly spaced repeats of the CCCTC DNA motif [1]
Knowing that Ctcf haploinsufficiency [119,120] or knockdown [118] induces hypermethylation, we proposed that Ctcf haploinsufficiency increased intron retention through a methylation-dependent mechanism [45], which may involve altering the kinetics of RNA polymerase II (RNAPII) elongation or chromatin looping
A broad putative role for CTCF in regulating diverse histone modifications could be achieved via PARP1 and PARylation [65]. These findings argue for a plausible link between CTCFassociated histone modifications and pre-mRNA splicing outcome, which might involve regulation of RNAPII kinetics and/or splicing factor recruitment via chromatinbinding proteins
Summary
CTCF – an old playerCCCTC-binding factor (CTCF) was first identified as a nuclear DNA-binding protein, which negatively regulates chicken c-myc expression by interacting with three regularly spaced repeats of the CCCTC DNA motif [1]. Such interactions are involved in some CTCF activities including CTCF dimerization, distal genomic binding sites, chromatin looping and gene regulation [9,10,11,12].
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