Author:
Siam Ahmad,Baker Mai,Amit Leah,Regev Gal,Rabner Alona,Najar Rauf Ahmad,Bentata Mercedes,Dahan Sara,Cohen Klil,Araten Sarah,Nevo Yuval,Kay Gillian,Mandel-Gutfreund Yael,Salton Maayan
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.
Funder
Israeli Cancer Association
Israeli Planning and Budgeting Committee
Israel Science Foundation
Core Laboratory Grant Program launched by Danyel Biotech
Illumina Channel Partner in Israel
Publisher
Cold Spring Harbor Laboratory
Cited by
30 articles.
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