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

Ahmad Siam; Mai Baker; Leah Amit; Gal Regev; Alona Rabner; Rauf Ahmad Najar; Mercedes Bentata; Sara Dahan; Klil Cohen; Sarah Araten; Yuval Nevo; Gillian Kay; Yael Mandel-Gutfreund; Maayan Salton

doi:10.1261/rna.069856.118

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

Ahmad Siam, Mai Baker, Leah Amit, Gal Regev, Alona Rabner, Rauf Ahmad Najar, Mercedes Bentata, Sara Dahan, Klil Cohen, Sarah Araten, Yuval Nevo, Gillian Kay, Yael Mandel-Gutfreund, Maayan Salton^*

^*Corresponding author for this work

Department of Biochemistry and Molecular Biology

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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 hnRNPM 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.

Original language	American English
Pages (from-to)	813-824
Number of pages	12
Journal	RNA
Volume	27
Issue number	5
DOIs	https://doi.org/10.1261/rna.069856.118
State	Published - 2019

Bibliographical note

Funding Information:
We thank Chonghui Cheng and Rotem Karni for valuable discussion. We thank Abed Nasereddin and Idit Shiff from the Genomic Applications Laboratory, The Core Research Facility, The Faculty of Medicine - Ein Kerem, The Hebrew University of Jerusalem, Israel, for their professional advice and RNA-seq service. We thank Amina Jbara for guidance on scratch assay technique. We thank Chonghui Cheng for the hnRNP M plasmid and Alberto Kornblihtt for slow RNAPII plasmids. This work was in part supported by the Israeli Cancer Association, Alon Award by the Israeli Planning and Budgeting Committee (PBC), and the Israel Science Foundation (ISF 1154/17). The RNA-seq reagents were funded by a Core Laboratory Grant Program launched by Danyel Biotech, the authorized Illumina Channel Partner in Israel.

Publisher Copyright:
© 2019 Siam et al.

Keywords

Alternative splicing
Chromatin
Pre-mRNA splicing

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10.1261/rna.069856.118

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title = "Regulation of alternative splicing by p300-mediated acetylation of splicing factors",

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 hnRNPM 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.",

keywords = "Alternative splicing, Chromatin, Pre-mRNA splicing",

author = "Ahmad Siam and Mai Baker and Leah Amit and Gal Regev and Alona Rabner and Najar, {Rauf Ahmad} and Mercedes Bentata and Sara Dahan and Klil Cohen and Sarah Araten and Yuval Nevo and Gillian Kay and Yael Mandel-Gutfreund and Maayan Salton",

note = "Funding Information: We thank Chonghui Cheng and Rotem Karni for valuable discussion. We thank Abed Nasereddin and Idit Shiff from the Genomic Applications Laboratory, The Core Research Facility, The Faculty of Medicine - Ein Kerem, The Hebrew University of Jerusalem, Israel, for their professional advice and RNA-seq service. We thank Amina Jbara for guidance on scratch assay technique. We thank Chonghui Cheng for the hnRNP M plasmid and Alberto Kornblihtt for slow RNAPII plasmids. This work was in part supported by the Israeli Cancer Association, Alon Award by the Israeli Planning and Budgeting Committee (PBC), and the Israel Science Foundation (ISF 1154/17). The RNA-seq reagents were funded by a Core Laboratory Grant Program launched by Danyel Biotech, the authorized Illumina Channel Partner in Israel. Publisher Copyright: {\textcopyright} 2019 Siam et al.",

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language = "American English",

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AU - Siam, Ahmad

AU - Baker, Mai

AU - Amit, Leah

AU - Regev, Gal

AU - Rabner, Alona

AU - Najar, Rauf Ahmad

AU - Bentata, Mercedes

AU - Dahan, Sara

AU - Cohen, Klil

AU - Araten, Sarah

AU - Nevo, Yuval

AU - Kay, Gillian

AU - Mandel-Gutfreund, Yael

AU - Salton, Maayan

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PY - 2019

Y1 - 2019

N2 - 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 hnRNPM 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.

AB - 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 hnRNPM 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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DO - 10.1261/rna.069856.118

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JO - RNA

JF - RNA

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ER -

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

Abstract

Bibliographical note

Keywords

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