Dysregulated RNA polyadenylation contributes to metabolic impairment in non-alcoholic fatty liver disease
Abstract Pre-mRNA processing is an essential mechanism for the generation of mature mRNA and the regulation of gene expression in eukaryotic cells. While defects in pre-mRNA processing have been implicated in a number of diseases their involvement in metabolic pathologies is still unclear. Here, we...
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| Veröffentlicht in: | Nucleic acids research 2022-04, Vol.50 (6), p.3379-3393 |
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| creator | Jobbins, Andrew M Haberman, Nejc Artigas, Natalia Amourda, Christopher Paterson, Helen A B Yu, Sijia Blackford, Samuel J I Montoya, Alex Dore, Marian Wang, Yi-Fang Sardini, Alessandro Cebola, Inês Zuber, Johannes Rashid, Sheikh Tamir Lenhard, Boris Vernia, Santiago |
| description | Abstract
Pre-mRNA processing is an essential mechanism for the generation of mature mRNA and the regulation of gene expression in eukaryotic cells. While defects in pre-mRNA processing have been implicated in a number of diseases their involvement in metabolic pathologies is still unclear. Here, we show that both alternative splicing and alternative polyadenylation, two major steps in pre-mRNA processing, are significantly altered in non-alcoholic fatty liver disease (NAFLD). Moreover, we find that Serine and Arginine Rich Splicing Factor 10 (SRSF10) binding is enriched adjacent to consensus polyadenylation motifs and its expression is significantly decreased in NAFLD, suggesting a role mediating pre-mRNA dysregulation in this condition. Consistently, inactivation of SRSF10 in mouse and human hepatocytes in vitro, and in mouse liver in vivo, was found to dysregulate polyadenylation of key metabolic genes such as peroxisome proliferator-activated receptor alpha (PPARA) and exacerbate diet-induced metabolic dysfunction. Collectively our work implicates dysregulated pre-mRNA polyadenylation in obesity-induced liver disease and uncovers a novel role for SRSF10 in this process. |
| doi_str_mv | 10.1093/nar/gkac165 |
| format | Article |
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Pre-mRNA processing is an essential mechanism for the generation of mature mRNA and the regulation of gene expression in eukaryotic cells. While defects in pre-mRNA processing have been implicated in a number of diseases their involvement in metabolic pathologies is still unclear. Here, we show that both alternative splicing and alternative polyadenylation, two major steps in pre-mRNA processing, are significantly altered in non-alcoholic fatty liver disease (NAFLD). Moreover, we find that Serine and Arginine Rich Splicing Factor 10 (SRSF10) binding is enriched adjacent to consensus polyadenylation motifs and its expression is significantly decreased in NAFLD, suggesting a role mediating pre-mRNA dysregulation in this condition. Consistently, inactivation of SRSF10 in mouse and human hepatocytes in vitro, and in mouse liver in vivo, was found to dysregulate polyadenylation of key metabolic genes such as peroxisome proliferator-activated receptor alpha (PPARA) and exacerbate diet-induced metabolic dysfunction. Collectively our work implicates dysregulated pre-mRNA polyadenylation in obesity-induced liver disease and uncovers a novel role for SRSF10 in this process.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkac165</identifier><identifier>PMID: 35293570</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Animals ; Cell Cycle Proteins - metabolism ; Gene regulation, Chromatin and Epigenetics ; Hepatocytes - metabolism ; Humans ; Liver - metabolism ; Mice ; Non-alcoholic Fatty Liver Disease - genetics ; Non-alcoholic Fatty Liver Disease - pathology ; Polyadenylation ; Repressor Proteins - metabolism ; RNA Precursors - genetics ; RNA Precursors - metabolism ; RNA Splicing ; Serine-Arginine Splicing Factors - metabolism</subject><ispartof>Nucleic acids research, 2022-04, Vol.50 (6), p.3379-3393</ispartof><rights>The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. 2022</rights><rights>The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c412t-1744113bef14845877cc4c797364ab7bf703fc2defa359263a562f1251b84c0e3</citedby><cites>FETCH-LOGICAL-c412t-1744113bef14845877cc4c797364ab7bf703fc2defa359263a562f1251b84c0e3</cites><orcidid>0000-0002-1114-1509 ; 0000-0001-6728-5555</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8989518/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8989518/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,1598,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/35293570$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jobbins, Andrew M</creatorcontrib><creatorcontrib>Haberman, Nejc</creatorcontrib><creatorcontrib>Artigas, Natalia</creatorcontrib><creatorcontrib>Amourda, Christopher</creatorcontrib><creatorcontrib>Paterson, Helen A B</creatorcontrib><creatorcontrib>Yu, Sijia</creatorcontrib><creatorcontrib>Blackford, Samuel J I</creatorcontrib><creatorcontrib>Montoya, Alex</creatorcontrib><creatorcontrib>Dore, Marian</creatorcontrib><creatorcontrib>Wang, Yi-Fang</creatorcontrib><creatorcontrib>Sardini, Alessandro</creatorcontrib><creatorcontrib>Cebola, Inês</creatorcontrib><creatorcontrib>Zuber, Johannes</creatorcontrib><creatorcontrib>Rashid, Sheikh Tamir</creatorcontrib><creatorcontrib>Lenhard, Boris</creatorcontrib><creatorcontrib>Vernia, Santiago</creatorcontrib><title>Dysregulated RNA polyadenylation contributes to metabolic impairment in non-alcoholic fatty liver disease</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>Abstract
Pre-mRNA processing is an essential mechanism for the generation of mature mRNA and the regulation of gene expression in eukaryotic cells. While defects in pre-mRNA processing have been implicated in a number of diseases their involvement in metabolic pathologies is still unclear. Here, we show that both alternative splicing and alternative polyadenylation, two major steps in pre-mRNA processing, are significantly altered in non-alcoholic fatty liver disease (NAFLD). Moreover, we find that Serine and Arginine Rich Splicing Factor 10 (SRSF10) binding is enriched adjacent to consensus polyadenylation motifs and its expression is significantly decreased in NAFLD, suggesting a role mediating pre-mRNA dysregulation in this condition. Consistently, inactivation of SRSF10 in mouse and human hepatocytes in vitro, and in mouse liver in vivo, was found to dysregulate polyadenylation of key metabolic genes such as peroxisome proliferator-activated receptor alpha (PPARA) and exacerbate diet-induced metabolic dysfunction. Collectively our work implicates dysregulated pre-mRNA polyadenylation in obesity-induced liver disease and uncovers a novel role for SRSF10 in this process.</description><subject>Animals</subject><subject>Cell Cycle Proteins - metabolism</subject><subject>Gene regulation, Chromatin and Epigenetics</subject><subject>Hepatocytes - metabolism</subject><subject>Humans</subject><subject>Liver - metabolism</subject><subject>Mice</subject><subject>Non-alcoholic Fatty Liver Disease - genetics</subject><subject>Non-alcoholic Fatty Liver Disease - pathology</subject><subject>Polyadenylation</subject><subject>Repressor Proteins - metabolism</subject><subject>RNA Precursors - genetics</subject><subject>RNA Precursors - metabolism</subject><subject>RNA Splicing</subject><subject>Serine-Arginine Splicing Factors - metabolism</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2022</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>EIF</sourceid><recordid>eNp9kM9LwzAUx4Mobk5P3iUnL1KXn017Ecb8CUNB9BzSNN2ibVLSbND_3uqm6MXTg_c-7_seHwBOMbrEKKdTp8J0-a40TvkeGGOakoTlKdkHY0QRTzBi2Qgcdd0bQphhzg7BiHKSUy7QGNjrvgtmua5VNCV8fpzB1te9Ko3rh5b1DmrvYrDFOpoORg8bE1Xha6uhbVplQ2NchNZB512iau1XX7NKxdjD2m5MgKXtjOrMMTioVN2Zk12dgNfbm5f5fbJ4unuYzxaJZpjEBAvGMKaFqTDLGM-E0JppkQuaMlWIohKIVpqUplKU5ySliqekwoTjImMaGToBV9vcdl00ptTDf0HVsg22UaGXXln5d-LsSi79RmZ5lnOcDQEX2wAdfDfIqX52MZKfxuVgXO6MD_TZ73M_7LfiATjfAn7d_pv0AeAxjf0</recordid><startdate>20220408</startdate><enddate>20220408</enddate><creator>Jobbins, Andrew M</creator><creator>Haberman, Nejc</creator><creator>Artigas, Natalia</creator><creator>Amourda, Christopher</creator><creator>Paterson, Helen A B</creator><creator>Yu, Sijia</creator><creator>Blackford, Samuel J I</creator><creator>Montoya, Alex</creator><creator>Dore, Marian</creator><creator>Wang, Yi-Fang</creator><creator>Sardini, Alessandro</creator><creator>Cebola, Inês</creator><creator>Zuber, Johannes</creator><creator>Rashid, Sheikh Tamir</creator><creator>Lenhard, Boris</creator><creator>Vernia, Santiago</creator><general>Oxford University Press</general><scope>TOX</scope><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>5PM</scope><orcidid>https://orcid.org/0000-0002-1114-1509</orcidid><orcidid>https://orcid.org/0000-0001-6728-5555</orcidid></search><sort><creationdate>20220408</creationdate><title>Dysregulated RNA polyadenylation contributes to metabolic impairment in non-alcoholic fatty liver disease</title><author>Jobbins, Andrew M ; Haberman, Nejc ; Artigas, Natalia ; Amourda, Christopher ; Paterson, Helen A B ; Yu, Sijia ; Blackford, Samuel J I ; Montoya, Alex ; Dore, Marian ; Wang, Yi-Fang ; Sardini, Alessandro ; Cebola, Inês ; Zuber, Johannes ; Rashid, Sheikh Tamir ; Lenhard, Boris ; Vernia, Santiago</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c412t-1744113bef14845877cc4c797364ab7bf703fc2defa359263a562f1251b84c0e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2022</creationdate><topic>Animals</topic><topic>Cell Cycle Proteins - metabolism</topic><topic>Gene regulation, Chromatin and Epigenetics</topic><topic>Hepatocytes - metabolism</topic><topic>Humans</topic><topic>Liver - metabolism</topic><topic>Mice</topic><topic>Non-alcoholic Fatty Liver Disease - genetics</topic><topic>Non-alcoholic Fatty Liver Disease - pathology</topic><topic>Polyadenylation</topic><topic>Repressor Proteins - metabolism</topic><topic>RNA Precursors - genetics</topic><topic>RNA Precursors - metabolism</topic><topic>RNA Splicing</topic><topic>Serine-Arginine Splicing Factors - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Jobbins, Andrew M</creatorcontrib><creatorcontrib>Haberman, Nejc</creatorcontrib><creatorcontrib>Artigas, Natalia</creatorcontrib><creatorcontrib>Amourda, Christopher</creatorcontrib><creatorcontrib>Paterson, Helen A B</creatorcontrib><creatorcontrib>Yu, Sijia</creatorcontrib><creatorcontrib>Blackford, Samuel J I</creatorcontrib><creatorcontrib>Montoya, Alex</creatorcontrib><creatorcontrib>Dore, Marian</creatorcontrib><creatorcontrib>Wang, Yi-Fang</creatorcontrib><creatorcontrib>Sardini, Alessandro</creatorcontrib><creatorcontrib>Cebola, Inês</creatorcontrib><creatorcontrib>Zuber, Johannes</creatorcontrib><creatorcontrib>Rashid, Sheikh Tamir</creatorcontrib><creatorcontrib>Lenhard, Boris</creatorcontrib><creatorcontrib>Vernia, Santiago</creatorcontrib><collection>Oxford Journals Open Access Collection</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nucleic acids research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jobbins, Andrew M</au><au>Haberman, Nejc</au><au>Artigas, Natalia</au><au>Amourda, Christopher</au><au>Paterson, Helen A B</au><au>Yu, Sijia</au><au>Blackford, Samuel J I</au><au>Montoya, Alex</au><au>Dore, Marian</au><au>Wang, Yi-Fang</au><au>Sardini, Alessandro</au><au>Cebola, Inês</au><au>Zuber, Johannes</au><au>Rashid, Sheikh Tamir</au><au>Lenhard, Boris</au><au>Vernia, Santiago</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Dysregulated RNA polyadenylation contributes to metabolic impairment in non-alcoholic fatty liver disease</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2022-04-08</date><risdate>2022</risdate><volume>50</volume><issue>6</issue><spage>3379</spage><epage>3393</epage><pages>3379-3393</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><abstract>Abstract
Pre-mRNA processing is an essential mechanism for the generation of mature mRNA and the regulation of gene expression in eukaryotic cells. While defects in pre-mRNA processing have been implicated in a number of diseases their involvement in metabolic pathologies is still unclear. Here, we show that both alternative splicing and alternative polyadenylation, two major steps in pre-mRNA processing, are significantly altered in non-alcoholic fatty liver disease (NAFLD). Moreover, we find that Serine and Arginine Rich Splicing Factor 10 (SRSF10) binding is enriched adjacent to consensus polyadenylation motifs and its expression is significantly decreased in NAFLD, suggesting a role mediating pre-mRNA dysregulation in this condition. Consistently, inactivation of SRSF10 in mouse and human hepatocytes in vitro, and in mouse liver in vivo, was found to dysregulate polyadenylation of key metabolic genes such as peroxisome proliferator-activated receptor alpha (PPARA) and exacerbate diet-induced metabolic dysfunction. Collectively our work implicates dysregulated pre-mRNA polyadenylation in obesity-induced liver disease and uncovers a novel role for SRSF10 in this process.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>35293570</pmid><doi>10.1093/nar/gkac165</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-1114-1509</orcidid><orcidid>https://orcid.org/0000-0001-6728-5555</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Cell Cycle Proteins - metabolism Gene regulation, Chromatin and Epigenetics Hepatocytes - metabolism Humans Liver - metabolism Mice Non-alcoholic Fatty Liver Disease - genetics Non-alcoholic Fatty Liver Disease - pathology Polyadenylation Repressor Proteins - metabolism RNA Precursors - genetics RNA Precursors - metabolism RNA Splicing Serine-Arginine Splicing Factors - metabolism |
| title | Dysregulated RNA polyadenylation contributes to metabolic impairment in non-alcoholic fatty liver disease |
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