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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| Veröffentlicht in: | RNA (Cambridge) 2019-07, Vol.25 (7), p.813-824 |
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| creator | 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 |
| 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
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. |
| doi_str_mv | 10.1261/rna.069856.118 |
| format | Article |
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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.</description><identifier>ISSN: 1355-8382</identifier><identifier>EISSN: 1469-9001</identifier><identifier>DOI: 10.1261/rna.069856.118</identifier><identifier>PMID: 30988101</identifier><language>eng</language><publisher>United States: Cold Spring Harbor Laboratory Press</publisher><subject>Acetylation ; Acetyltransferase ; Alternative Splicing ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; CD44 antigen ; Chromatin ; Chromatin - genetics ; Chromatin - metabolism ; E1A-Associated p300 Protein - genetics ; E1A-Associated p300 Protein - metabolism ; Event-related potentials ; Exons ; Female ; Gene expression ; Gene Expression Regulation, Neoplastic ; Genomes ; Humans ; Hyaluronan Receptors - genetics ; Hyaluronan Receptors - metabolism ; Promoter Regions, Genetic ; RNA Splicing Factors - chemistry ; RNA Splicing Factors - genetics ; RNA Splicing Factors - metabolism ; Splicing factors ; Transcription elongation ; Transcription, Genetic ; Tumor Cells, Cultured</subject><ispartof>RNA (Cambridge), 2019-07, Vol.25 (7), p.813-824</ispartof><rights>2019 Siam et al.; Published by Cold Spring Harbor Laboratory Press for the RNA Society.</rights><rights>Copyright Cold Spring Harbor Laboratory Press Jul 2019</rights><rights>2019</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c463t-60a3fcc32f12916300fd35c851464e9f19e6604ea00835ca02f479bbaa3d63f53</citedby><cites>FETCH-LOGICAL-c463t-60a3fcc32f12916300fd35c851464e9f19e6604ea00835ca02f479bbaa3d63f53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6573785/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6573785/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30988101$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Siam, Ahmad</creatorcontrib><creatorcontrib>Baker, Mai</creatorcontrib><creatorcontrib>Amit, Leah</creatorcontrib><creatorcontrib>Regev, Gal</creatorcontrib><creatorcontrib>Rabner, Alona</creatorcontrib><creatorcontrib>Najar, Rauf Ahmad</creatorcontrib><creatorcontrib>Bentata, Mercedes</creatorcontrib><creatorcontrib>Dahan, Sara</creatorcontrib><creatorcontrib>Cohen, Klil</creatorcontrib><creatorcontrib>Araten, Sarah</creatorcontrib><creatorcontrib>Nevo, Yuval</creatorcontrib><creatorcontrib>Kay, Gillian</creatorcontrib><creatorcontrib>Mandel-Gutfreund, Yael</creatorcontrib><creatorcontrib>Salton, Maayan</creatorcontrib><title>Regulation of alternative splicing by p300-mediated acetylation of splicing factors</title><title>RNA (Cambridge)</title><addtitle>RNA</addtitle><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
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.</description><subject>Acetylation</subject><subject>Acetyltransferase</subject><subject>Alternative Splicing</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>CD44 antigen</subject><subject>Chromatin</subject><subject>Chromatin - genetics</subject><subject>Chromatin - metabolism</subject><subject>E1A-Associated p300 Protein - genetics</subject><subject>E1A-Associated p300 Protein - metabolism</subject><subject>Event-related potentials</subject><subject>Exons</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genomes</subject><subject>Humans</subject><subject>Hyaluronan Receptors - genetics</subject><subject>Hyaluronan Receptors - metabolism</subject><subject>Promoter Regions, Genetic</subject><subject>RNA Splicing Factors - chemistry</subject><subject>RNA Splicing Factors - genetics</subject><subject>RNA Splicing Factors - metabolism</subject><subject>Splicing factors</subject><subject>Transcription elongation</subject><subject>Transcription, Genetic</subject><subject>Tumor Cells, Cultured</subject><issn>1355-8382</issn><issn>1469-9001</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkUtLAzEUhYMotla3LmXAjZsZk8mjyUaQ4gsKgo91yGSSmjKd1Emm0H9vSmt9rBLu_e65JzkAnCNYoJKh665VBWSCU1YgxA_AEBEmcgEhOkx3TGnOMS8H4CSEeSri1D4GAwwF5wiiIXh9MbO-UdH5NvM2U000STK6lcnCsnHatbOsWmdLDGG-MLVT0dSZ0iauf4b2oFU6-i6cgiOrmmDOducIvN_fvU0e8-nzw9PkdpprwnDMGVTYao1Li0qBWNpga0w1p8kjMcIiYRiDxCgIeaorWFoyFlWlFK4ZthSPwM1Wd9lXyZs2bexUI5edW6huLb1y8m-ndR9y5leS0TEe843A1U6g85-9CVEuXNCmaVRrfB9kWSJYEgI5SejlP3Tu-_RTzYaiApPEsEQVW0p3PoTO2L0ZBOUmL5lG5DYvmfJKAxe_n7DHvwPCX2KrkVs</recordid><startdate>20190701</startdate><enddate>20190701</enddate><creator>Siam, Ahmad</creator><creator>Baker, Mai</creator><creator>Amit, Leah</creator><creator>Regev, Gal</creator><creator>Rabner, Alona</creator><creator>Najar, Rauf Ahmad</creator><creator>Bentata, Mercedes</creator><creator>Dahan, Sara</creator><creator>Cohen, Klil</creator><creator>Araten, Sarah</creator><creator>Nevo, Yuval</creator><creator>Kay, Gillian</creator><creator>Mandel-Gutfreund, Yael</creator><creator>Salton, Maayan</creator><general>Cold Spring Harbor Laboratory Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20190701</creationdate><title>Regulation of alternative splicing by p300-mediated acetylation of splicing factors</title><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></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c463t-60a3fcc32f12916300fd35c851464e9f19e6604ea00835ca02f479bbaa3d63f53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Acetylation</topic><topic>Acetyltransferase</topic><topic>Alternative Splicing</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>CD44 antigen</topic><topic>Chromatin</topic><topic>Chromatin - genetics</topic><topic>Chromatin - metabolism</topic><topic>E1A-Associated p300 Protein - genetics</topic><topic>E1A-Associated p300 Protein - metabolism</topic><topic>Event-related potentials</topic><topic>Exons</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Genomes</topic><topic>Humans</topic><topic>Hyaluronan Receptors - genetics</topic><topic>Hyaluronan Receptors - metabolism</topic><topic>Promoter Regions, Genetic</topic><topic>RNA Splicing Factors - chemistry</topic><topic>RNA Splicing Factors - genetics</topic><topic>RNA Splicing Factors - metabolism</topic><topic>Splicing factors</topic><topic>Transcription elongation</topic><topic>Transcription, Genetic</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Siam, Ahmad</creatorcontrib><creatorcontrib>Baker, Mai</creatorcontrib><creatorcontrib>Amit, Leah</creatorcontrib><creatorcontrib>Regev, Gal</creatorcontrib><creatorcontrib>Rabner, Alona</creatorcontrib><creatorcontrib>Najar, Rauf Ahmad</creatorcontrib><creatorcontrib>Bentata, Mercedes</creatorcontrib><creatorcontrib>Dahan, Sara</creatorcontrib><creatorcontrib>Cohen, Klil</creatorcontrib><creatorcontrib>Araten, Sarah</creatorcontrib><creatorcontrib>Nevo, Yuval</creatorcontrib><creatorcontrib>Kay, Gillian</creatorcontrib><creatorcontrib>Mandel-Gutfreund, Yael</creatorcontrib><creatorcontrib>Salton, Maayan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>RNA (Cambridge)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Siam, Ahmad</au><au>Baker, Mai</au><au>Amit, Leah</au><au>Regev, Gal</au><au>Rabner, Alona</au><au>Najar, Rauf Ahmad</au><au>Bentata, Mercedes</au><au>Dahan, Sara</au><au>Cohen, Klil</au><au>Araten, Sarah</au><au>Nevo, Yuval</au><au>Kay, Gillian</au><au>Mandel-Gutfreund, Yael</au><au>Salton, Maayan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulation of alternative splicing by p300-mediated acetylation of splicing factors</atitle><jtitle>RNA (Cambridge)</jtitle><addtitle>RNA</addtitle><date>2019-07-01</date><risdate>2019</risdate><volume>25</volume><issue>7</issue><spage>813</spage><epage>824</epage><pages>813-824</pages><issn>1355-8382</issn><eissn>1469-9001</eissn><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
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.</abstract><cop>United States</cop><pub>Cold Spring Harbor Laboratory Press</pub><pmid>30988101</pmid><doi>10.1261/rna.069856.118</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | RNA (Cambridge), 2019-07, Vol.25 (7), p.813-824 |
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| language | eng |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Acetylation Acetyltransferase Alternative Splicing Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology CD44 antigen Chromatin Chromatin - genetics Chromatin - metabolism E1A-Associated p300 Protein - genetics E1A-Associated p300 Protein - metabolism Event-related potentials Exons Female Gene expression Gene Expression Regulation, Neoplastic Genomes Humans Hyaluronan Receptors - genetics Hyaluronan Receptors - metabolism Promoter Regions, Genetic RNA Splicing Factors - chemistry RNA Splicing Factors - genetics RNA Splicing Factors - metabolism Splicing factors Transcription elongation Transcription, Genetic Tumor Cells, Cultured |
| title | Regulation of alternative splicing by p300-mediated acetylation of splicing factors |
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