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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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cold Spring Harbor Laboratory Press
2019
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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. |
format | Online Article Text |
id | pubmed-6573785 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Cold Spring Harbor Laboratory Press |
record_format | MEDLINE/PubMed |
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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