Regulation of Alternative Splicing Through Coupling with Transcription and Chromatin Structure

Abstract

Alternative precursor messenger RNA (pre-mRNA) splicing plays a pivotal role in the flow of genetic information from DNA to proteins by expanding the coding capacity of genomes. Regulation of alternative splicing is as important as regulation of transcription to determine cell- and tissue-specific features, normal cell functioning, and responses of eukaryotic cells to external cues. Its importance is confirmed by the evolutionary conservation and diversification of alternative splicing and the fact that its deregulation causes hereditary disease and cancer. This review discusses the multiple layers of cotranscriptional regulation of alternative splicing in which chromatin structure, DNA methylation, histone marks, and nucleosome positioning play a fundamental role in providing a dynamic scaffold for interactions between the splicing and transcription machineries. We focus on evidence for how the kinetics of RNA polymerase II (RNAPII) elongation and the recruitment of splicing factors and adaptor proteins to chromatin components act in coordination to regulate alternative splicing.

A molecular signature for delayed graft function

“…Alternative splicing is a common post‐transcriptional modification that enables cells to increase protein diversity from a single copy of a gene by generation of unique coding transcripts or regulatory noncoding RNAs. These can be affected by changes in DNA methylation status and GC content at the intron–exon boundaries, ultimately affecting both splicing outcomes, alternative splicing networks and affecting writing and/or maintenance of epigenetic marks and changes in chromatin status (Francisco & Baralle, 2017; Shiran Naftelberg, Ast, & Kornblihtt, 2015). Transcripts associated with chromatin remodelling were significantly affected by the perfusion status in our cohort and included polycomb group genes (BMI1, SUZ12, TRIM27); chromobox/HP1 homologs (CBX4, CBX8); bromodomain proteins (BRD2, WDR11); ING family members (ING1, INg2, ING4) and PHF21B.…”

Characterization of the Regulation of CD46 RNA Alternative Splicing

“…The longer time to transcribe the endogenous compared with the minigene's intron 13 (3173 versus 600 bp) could also facilitate recruitment of this repressor. Furthermore, chromatin structures, histone modifications, and different promoters could also contribute to differences in exon 13 inclusion between endogenous and plasmid-derived CD46 transcripts (38,71). Thus, the CD46 exon 13 minigene does not completely reconstitute the endogenous regulation, but it allowed the identification of many general cis-acting elements.…”

Altérations de l’épissage et maladies rares

“…La reconnaissance d'un exon et son inclusion dépend de la combinaison des facteurs d'épis-sage impliqués (présence et concentration cellulaire). Il est par ailleurs maintenant bien établi que d'autres conditions peuvent influencer le choix d'inclusion ou d'exclusion d'exons alternatifs comme des modifications des histones [9], ou la vitesse de transcription [10].…”

“…La réaction d'épissage se déroule en plusieurs étapes présentées sur la Figure 2B. Il est maintenant clairement établi que la réaction d'épissage a lieu simultanément à la transcription et qu'un certain nombre de protéines interviennent à la fois dans la régulation de l'épissage et celle de la transcription [9]. Cette reconnaissance des exons par le splicéosome est assortie d'un niveau supplémentaire de régulation qui a pour fonction de renforcer la reconnaissance des sites d'épissage, ou au contraire de la diminuer.…”