Date Published:

Jul

Abstract:

Splicing of precursor mRNA (pre-mRNA) is an important regulatory step in gene expression. Recent evidence points to a regulatory role of chromatin-related proteins in alternative splicing regulation. Using an unbiased approach, we have identified the acetyltransferase p300 as a key chromatin-related regulator of alternative splicing. p300 promotes genome-wide exon inclusion in both a transcription-dependent and -independent manner. Using CD44 as a paradigm, we found that p300 regulates alternative splicing by modulating the binding of splicing factors to pre-mRNA. Using a tethering strategy, we found that binding of p300 to the CD44 promoter region promotes CD44v exon inclusion independently of RNAPII transcriptional elongation rate. Promoter-bound p300 regulates alternative splicing by acetylating splicing factors, leading to exclusion of hnRNP M from CD44 pre-mRNA and activation of Sam68. p300-mediated CD44 alternative splicing reduces cell motility and promotes epithelial features. Our findings reveal a chromatin-related mechanism of alternative splicing regulation and demonstrate its impact on cellular function.

Notes:

1469-9001Siam, AhmadBaker, MaiAmit, LeahRegev, GalRabner, AlonaNajar, Rauf AhmadBentata, MercedesDahan, SaraCohen, KlilAraten, SarahNevo, YuvalKay, GillianMandel-Gutfreund, YaelSalton, MaayanJournal ArticleResearch Support, Non-U.S. Gov'tRNA. 2019 Jul;25(7):813-824. doi: 10.1261/rna.069856.118. Epub 2019 Apr 15.

PubMed