CTCF-promoted RNA polymerase II pausing links DNA methylation to splicing

By S. Shukla, Ersen Kavak, Melissa Gregory, Masahiko Imashimizu, Bojan Shutinoski, M. Kashlev, Philipp Oberdoerffer, Rickard Sandberg, Shalini Oberdoerffer. Nature, 2011

1,006 citations recorded by the source corpus.

Alternative splicing of pre-messenger RNA is a key feature of transcriptome expansion in eukaryotic cells, yet its regulation is poorly understood. Spliceosome assembly occurs co-transcriptionally, raising the possibility that DNA structure may directly influence alternative splicing. Supporting such an association, recent reports have identified distinct histone methylation patterns, elevated nucleosome occupancy and enriched DNA methylation at exons relative to introns. Moreover, the rate of transcription elongation has been linked to alternative splicing. Here we provide the first evidence that a DNA-binding protein, CCCTC-binding factor (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, and genome-wide. We further show that CTCF binding to CD45 exon 5 is inhibited by DNA methylation, leading to reciprocal effects on exon 5 inclusion. These findings provide a mechanistic basis for developmental regulation of splicing outcome through heritable epigenetic marks.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/bccbc85962eb70189ec7c80cc8db0c3f773ca2ae

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Citations in the corpus

• Deep sequencing of subcellular RNA fractions shows splicing to be predominantly co-transcriptional in the human genome but inefficient for lncRNAs (2012, background): “2010), and CTCF-mediated local RNA polymerase II (Pol II) pausing has been shown to influence alternative splicing (Shukla et al. 2011).”
• Widespread plasticity in CTCF occupancy linked to DNA methylation (2012, neutral): “…patterns are largely invariant between cell types (Kim et al. 2007; Cuddapah et al. 2008; Heintzman et al. 2009), though diverse regulatory mechanisms at individual loci have been described (Lefevre et al. 2008; Sekimata et al. 2009; Witcher and Emerson 2009; Lai et al. 2010; Shukla et al. 2011).”
• High-resolution genome-wide DNA methylation maps of mouse primary female dermal fibroblasts and keratinocytes (2014, neutral): “[49].”