2017
DOI: 10.1038/ncomms15134
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Intron retention is regulated by altered MeCP2-mediated splicing factor recruitment

Abstract: While intron retention (IR) is considered a widely conserved and distinct mechanism of gene expression control, its regulation is poorly understood. Here we show that DNA methylation directly regulates IR. We also find reduced occupancy of MeCP2 near the splice junctions of retained introns, mirroring the reduced DNA methylation at these sites. Accordingly, MeCP2 depletion in tissues and cells enhances IR. By analysing the MeCP2 interactome using mass spectrometry and RNA co-precipitation, we demonstrate that … Show more

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Cited by 97 publications
(114 citation statements)
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References 63 publications
(109 reference statements)
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“…Changing the GC content in and around retained introns had only the potential to repress, but not to enhance splicing ( Fig S2H). A differential effect of CG vs GC dinucleotides in the exon could be observed also here ( Fig 2H; p=9.0x10 -11 , Wilcoxon signed-rank test), supporting recent observations showing a relationship between loss of DNA methylation and increased intron retention (Kim et al, 2018;Wong et al, 2017).…”
Section: Resultssupporting
confidence: 91%
“…Changing the GC content in and around retained introns had only the potential to repress, but not to enhance splicing ( Fig S2H). A differential effect of CG vs GC dinucleotides in the exon could be observed also here ( Fig 2H; p=9.0x10 -11 , Wilcoxon signed-rank test), supporting recent observations showing a relationship between loss of DNA methylation and increased intron retention (Kim et al, 2018;Wong et al, 2017).…”
Section: Resultssupporting
confidence: 91%
“…Interestingly, for two genes (SF3B1 and SPTA1), blocking the decoy exon essentially eliminated IR, suggesting that the decoy pathway may be the sole determinant of IR. In contrast, IR was not completely abrogated by antisense treatment in the OGT gene, consistent with the co-existence of decoy-independent IR mechanisms (Monteuuis et al 2019;Braun et al 2017;Cho et al 2014;Wong et al 2017). Finally, in the one case tested, OGT, decreased IR was accompanied by increases in spliced RNA and protein expression.…”
Section: Discussionmentioning
confidence: 59%
“…We anticipate that analogous subsets of IR events might be regulated by decoy mechanisms in other developmental or physiological contexts. Possible candidates could include differentiating granulocytes (Wong et al 2013; Wong et al 2017), activated T cells (Ni et al 2016), stimulated neurons (Mauger et al 2016), cells subjected to proteotoxic stress (Shalgi et al 2014), proliferating vs differentiated muscle cells (Llorian et al 2016), differentiating germ cells (Naro et al 2017), etc. Identifying the RBPs that regulate these decoy-dependent programs will be an important goal of future studies in this area.…”
Section: Discussionmentioning
confidence: 99%
“…How these sub-programs are regulated is not well understood. Recent studies have implicated transcription rate/pausing (Braunschweig et al 2014), specific splicing factors (SRSF4 and HNRNPLL), and DNA and protein methylation factors (by MECP2, in granulocytes, and by PRMT5, in glioblastoma) as important effectors of IR (Cho et al 2014; Boutz et al 2015; Braun et al 2017; Wong et al 2017). In the brain, signaling-dependent splicing was observed to require NMDA-type glutamate receptor or calmodulin-dependent protein kinase pathways for removal of retained introns upon neuronal activation (Mauger et al 2016).…”
Section: Introductionmentioning
confidence: 99%