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Regulation of alternative splicing by p300-mediated acetylation of splicing factors

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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6573785/
https://www.ncbi.nlm.nih.gov/pubmed/30988101
http://dx.doi.org/10.1261/rna.069856.118
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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
author_facet 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
author_sort Siam, Ahmad
collection PubMed
description 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.
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spelling pubmed-65737852020-07-01 Regulation of alternative splicing by p300-mediated acetylation of splicing factors 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 RNA Article 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. Cold Spring Harbor Laboratory Press 2019-07 /pmc/articles/PMC6573785/ /pubmed/30988101 http://dx.doi.org/10.1261/rna.069856.118 Text en © 2019 Siam et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by the RNA Society for the first 12 months after the full-issue publication date (see http://rnajournal.cshlp.org/site/misc/terms.xhtml). After 12 months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Article
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
Regulation of alternative splicing by p300-mediated acetylation of splicing factors
title Regulation of alternative splicing by p300-mediated acetylation of splicing factors
title_full Regulation of alternative splicing by p300-mediated acetylation of splicing factors
title_fullStr Regulation of alternative splicing by p300-mediated acetylation of splicing factors
title_full_unstemmed Regulation of alternative splicing by p300-mediated acetylation of splicing factors
title_short Regulation of alternative splicing by p300-mediated acetylation of splicing factors
title_sort regulation of alternative splicing by p300-mediated acetylation of splicing factors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6573785/
https://www.ncbi.nlm.nih.gov/pubmed/30988101
http://dx.doi.org/10.1261/rna.069856.118
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