Abstract
BackgroundPre-mRNA splicing occurs mainly co-transcriptionally, and both nucleosome density and histone modifications have been proposed to play a role in splice site recognition and regulation. However, the extent and mechanisms behind this interplay remain poorly understood.ResultsWe use transcriptomic and epigenomic data generated by the ENCODE project to investigate the association between chromatin structure and alternative splicing. We find a strong and significant positive association between H3K9ac, H3K27ac, H3K4me3, epigenetic marks characteristic of active promoters, and exon inclusion in a small but well-defined class of exons, representing approximately 4 % of all regulated exons. These exons are systematically maintained at comparatively low levels of inclusion across cell types, but their inclusion is significantly enhanced in particular cell types when in physical proximity to active promoters.ConclusionHistone modifications and other chromatin features that activate transcription can be co-opted to participate in the regulation of the splicing of exons that are in physical proximity to promoter regions.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0797-8) contains supplementary material, which is available to authorized users.
Highlights
Pre-Messenger ribonucleic acid (mRNA) splicing occurs mainly co-transcriptionally, and both nucleosome density and histone modifications have been proposed to play a role in splice site recognition and regulation
We identified 1,688 exons regulated between these two cell lines (1,066 more included in Gm12878 and 622 more included in K562, P value
To investigate the two alternatives, we performed k-means clustering on the sets of more and less included exons, based on the levels of the five chromatin features that we found significantly associated with differential exon inclusion
Summary
Pre-mRNA splicing occurs mainly co-transcriptionally, and both nucleosome density and histone modifications have been proposed to play a role in splice site recognition and regulation. Alternative pre-mRNA splicing is assumed to expand the diversity of mRNAs encoded in the genome. The prevalence of alternative splicing increases from invertebrates to vertebrates [1] and is high in the immune and nervous systems, where high diversity of molecular repertoires is necessary for cell identity [2]. Whether an alternative exon is included or excluded in a mature RNA is considered a matter of combinatorial control, involving splice sites, additional binding sites, and the factors that recognize them [3]. Some splicing factors are known to interact with modified histone tails, and
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