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4sU metabolic labeled transcripts in mESCs

ABSTRACT: We carried out an extensive functional genomics analysis to elucidate the roles, if any, of splicing at enhancer-associated lincRNA loci (elincRNA). While we found little evidence supporting conservation of elincRNA exons, their splice sites and other splicing associated motifs accumulated significantly fewer mutations than neutrally evolving regions, suggesting that selection has acted to preserve their splicing. We showed that in contrast to other lincRNAs, not only were multi-exonic elincRNAs efficiently and rapidly spliced, they were also specifically associated with enhanced expression of proximal genes and increased local chromosomal interactions. Enrichment of chromatin signatures associated with high enhancer activity at these loci further supports the contribution of elincRNA splicing to enhancer function. Our results elucidate the previously observed evolutionary constraint at elincRNA splice sites, but not their exons, and corroborate the impact of elincRNA splicing modulation on neighboring gene expression regulation, highlighting an unexpected contribution of elincRNA splicing to enhancer function.

ORGANISM(S): Mus musculus

PROVIDER: GSE111951 | GEO | 2018/03/17

REPOSITORIES: GEO

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Mouse Alt-Splice Tissue Panel (Brain vs Non-Brain)

Project description:22 Normal adult mouse tissues on custom alternative transcript sensitive Affymetrix microarray used to address differeneces in tissue specific alternative splicing. Abstract: Alternative splicing contributes to both gene regulation and protein diversity. To discover broad relationships between regulation of alternative splicing and sequence conservation, we applied a systems approach, using oligonucleotide microarrays designed to capture splicing information across the mouse genome. In a set of 22 adult tissues, we observe expression of RNA containing at least two alternative splice junctions for about a third of the 3200 alternative events we could detect. Statistical comparisons identify 171 cassette exons whose inclusion or skipping is different in brain relative to other tissues, and another 28 exons whose splicing is different in muscle. A subset of these exons is associated with unusual blocks of intron sequence whose conservation in vertebrates rivals that of protein-coding exons. By focusing on sets of exons with similar regulatory patterns, we have identified new sequence motifs implicated in brain and muscle splicing regulation. Of note is a motif strikingly similar to the branchpoint consensus, but which is located downstream of the 5' splice site of exons included in muscle. Analysis of three paralogous membrane-associated guanylate kinase (MAGUK) genes reveals that each contains a paralogous tissue regulated exon with a similar tissue inclusion pattern. While the intron sequences flanking these exons remain highly conserved among mammalian orthologs, the paralogous flanking intron sequences have diverged considerably, suggesting unusually complex evolution of the regulation of alternative splicing in multigene families. Keywords: Alternative splicing isoform specific, adult mouse tissues

2006-01-19 | GSE3063 | GEO

N6-Methyladenosine mediates alternative intron/exon inclusion in the nascent transcriptome [4sU-seq]

Project description:N6-methyladenosines (m6A) are stoichiometrically deposited on exons of nearly one third of RNA Pol II transcriptome, mainly catalysed by METTL3/14 complex. However, neither the intronic methylation pattern and its functional relevance nor the immediate response upon m6A loss have been fully understood. Here we applied MeRIP-seq on mESC nascent transcriptome and thus revealed that approximately 6-10% of m6A peaks occurred at intronic regions, preferentially the conserved and alternative exon/intron part of longer introns, proximately to 5’-splice sites. These intronic m6A deposition correlates with both Rbm15 binding and H3K36me3. Moreover, coupled 4sU-seq with METTL3 dTAG system in mESC, we found that m6A mediates alternative exon/intron inclusive in nascent transcriptome. Intriguingly, m6A self-regulation including writers and readers are early response and partially contributed by alternative splicing changes. Collectively, our study presents a unified model that m6A mediates alternative splicing, and dTAG METTL3 opens an avenue to interrogate the direct response of functional m6A disruption.

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SF3B1 association with chromatin determines splicing outcomes

Project description:Much remains unknown concerning the mechanism by which the splicing machinery pinpoints short exons within intronic sequences and how splicing factors are directed to their pre-mRNA targets. Part of the explanation probably lies in differences in chromatin organization between exons and introns. Proteomic, co-immunoprecipitation, and sedimentation analyses described here indicated that SF3B1, an essential splicing component of the U2 snRNP complex, is strongly associated with nucleosomes. ChIP-seq and RNA-seq analyses revealed that SF3B1 is specifically bound to nucleosomes located at exonic positions. SF3B1 binding is enriched at nucleosomes positioned over short exons flanked by long introns that are also characterized by differential GC content between exons and introns. Disruption of SF3B1 binding to such nucleosomes affected the splicing of these exons similarly to inhibition of SF3B1 expression. Our findings suggest that the association of SF3B1 with nucleosomes is functionally important for splice site recognition and that SF3B1 conveys splicing-relevant information embedded in chromatin structure. MNase-seq on Input and SF3B1 pull-down, mRNA-seq on control and SF3B1 si-RNA treated cells as well as on TSA (Trichostatin A) treated and untreated cells.

2015-04-22 | E-GEOD-65644 | biostudies-arrayexpress

SF3B1 association with chromatin determines splicing outcomes

2015-04-22 | GSE65644 | GEO

Branch point evolution controls species-specific alternative splicing and regulates long term potentiation

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2007-12-08 | GSE9734 | GEO

Profiling lariat intermediates reveals genetic determinants of early and late co-transcriptional splicing

Project description:Long introns with short exons in vertebrate genes are thought to require spliceosome assembly across exons (exon definition), rather than introns, thereby requiring transcription of an exon to splice an upstream intron. Here, we developed CoLa-seq (co-transcriptional lariat sequencing) to investigate the timing and determinants of co-transcriptional splicing genome wide. Unexpectedly, 90% of all introns, including long introns, can splice before transcription of a downstream exon, indicating that exon definition is not obligatory for most human introns. Still, splicing timing varies dramatically across introns, and various genetic elements determine this variation. Strong U2AF2 binding to the polypyrimidine tract predicts early splicing, explaining exon definition-independent splicing. Together, our findings question the essentiality of exon definition and reveal features beyond intron and exon length that are determinative for splicing timing.

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2010-10-01 | E-MTAB-367 | biostudies-arrayexpress

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Position-dependent alternative splicing activity revealed by global profiling of alternative splicing events regulated by PTB (HJAY)

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