Epigenetics in Alternative Pre-mRNA Splicing

Abstract

Alternative splicing plays critical roles in differentiation, development and disease and is a major source for protein diversity in higher eukaryotes. Traditionally, analysis of alternative splicing regulation has focused on RNA sequence elements and their associated factors, but recent provocative studies point to a key function of chromatin structure and histone modifications in alternative splicing regulation. These insights suggest that epigenetic regulation not only determines what parts of the genome are expressed, but also how they are spliced.

RNA-Seq and human complex diseases: recent accomplishments and future perspectives

“…Histone modifications and nucleosome positioning are not only responsible for what portions of the genome are expressed, but they also contribute to determine how they are (alternatively) spliced. 85 It is evident that to better understand the interplay between epigenetic modifications and gene expression, as well as to assess their impact on human complex traits and common diseases, further combined studies (RNA-Seq and other NGS applications) are needed. To this purpose, a growing number of studies is currently showing that the integration of data derived from ChIP-(and its subapplications such as MeDIP-Seq or Methyl-Seq) and RNA-Seq analyses is the way forward.…”

Histone H3K36 methylation regulates pre-mRNA splicing inSaccharomyces cerevisiae

“…[5][6][7][8][9] Mounting evidence supports a model in which pre-mRNA splicing is tightly coordinated with transcription to ensure precise and efficient gene expression. 10,11 The fact that pre-mRNA splicing occurs cotemporally with RNA Pol II-dependent gene transcription indicates that spliceosome assembly and subsequent catalytic steps take place in the context of a dynamic chromatin environment. There are currently 2 nonmutually exclusive proposed mechanisms for coupling transcription and RNA splicing.…”

“…The first is a recruitment model in which RNA Pol II and/or transcription-related proteins, either directly or indirectly, physically recruit splicing factors to the nascent transcript leading to specific splicing outcomes. 10,11 The second is a kinetic coupling model that explains how splicing can be impacted by transcription elongation rates. The splicing of a given intron is enhanced when the rate of elongation is slow because the splicing machinery has more time to access the splice sites.…”

L’épissage des ARN pré-messagers : quand le splicéosome perd pied

“…Plusieurs catégories de tels agents peuvent être envisagées (pour revue, voir [45,46]) : -des molécules ciblant spécifiquement des protéines du splicéosome comme SF3B1 (spliceostatine, pladienolide, meayamycine), ainsi que de nombreuses autres ; -d'autres composés aux effets moins spécifiques sur l'épissage, comme le clotrimazole, l'indole, les dérivés de la diospyrine, ou encore les camptothécines, le butyrate ou le valproate de sodium ou le resvératrol. Du fait du couplage entre transcription et épissage, du rôle de modifications épigénétiques sur les activités transcriptionnelles et d'épissage [47], et de l'influence de paramètres épigénétiques sur l'activité du splicéo-some [48], il serait intéressant d'évaluer également le potentiel correctif de « drogues épigénétiques » additionnelles (inhibitrices des ADN méthyl-transférases par exemple).…”