Homocysteine Induces Collagen I Expression by Downregulating Histone Methyltransferase G9a
Hyperhomocysteinemia (HHcy) leads to several clinical manifestations including hepatic fibrosis. Excess deposition of extracellular matrix (ECM) components including collagen is the eponymous lesion of liver fibrosis. In this study, we demonstrated that elevated concentration of Hcy induced the expr...
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| creator | Lei, Wenjing Long, Yanjun Li, Shuang Liu, Ze Zhu, Fengxin Hou, Fan Fan Nie, Jing |
| description | Hyperhomocysteinemia (HHcy) leads to several clinical manifestations including hepatic fibrosis. Excess deposition of extracellular matrix (ECM) components including collagen is the eponymous lesion of liver fibrosis. In this study, we demonstrated that elevated concentration of Hcy induced the expression of collagen type I in cultured human liver cells as well as in liver tissue of HHcy mice. Meanwhile, Hcy inhibited the expression of histone methyltransferase G9a. Mechanistically, silencing endogenous G9a by siRNA enhanced the promoter activity of COL1A1 in LO2 cells. Conversely, overexpressing G9a inhibited the promoter activity of COL1A1. CHIP assay demonstrated that G9a binds to the neuron-restrictive silencer element (NRSE) on the promoter of COL1A1. Hcy treatment decreased the binding of G9a on NRSE, which in turn decreased the level of H3K9me2 on the promoter of COL1A1, led to upregulation of COL1A1. Taken together, these results provide a novel mechanism on explaining how HHcy promotes ECM production. |
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Excess deposition of extracellular matrix (ECM) components including collagen is the eponymous lesion of liver fibrosis. In this study, we demonstrated that elevated concentration of Hcy induced the expression of collagen type I in cultured human liver cells as well as in liver tissue of HHcy mice. Meanwhile, Hcy inhibited the expression of histone methyltransferase G9a. Mechanistically, silencing endogenous G9a by siRNA enhanced the promoter activity of COL1A1 in LO2 cells. Conversely, overexpressing G9a inhibited the promoter activity of COL1A1. CHIP assay demonstrated that G9a binds to the neuron-restrictive silencer element (NRSE) on the promoter of COL1A1. Hcy treatment decreased the binding of G9a on NRSE, which in turn decreased the level of H3K9me2 on the promoter of COL1A1, led to upregulation of COL1A1. Taken together, these results provide a novel mechanism on explaining how HHcy promotes ECM production.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0130421</identifier><identifier>PMID: 26192994</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Base Sequence ; Cancer ; Cell Line ; Cocaine ; Collagen ; Collagen (type I) ; Collagen Type I - genetics ; Deoxyribonucleic acid ; DNA ; DNA methylation ; Down-Regulation ; Epigenetics ; Extracellular matrix ; Fibrosis ; Gene expression ; Hepatocytes ; Histocompatibility Antigens - genetics ; Histocompatibility Antigens - metabolism ; Histone methyltransferase ; Histone-Lysine N-Methyltransferase - genetics ; Histone-Lysine N-Methyltransferase - metabolism ; Histones ; Histones - chemistry ; Histones - metabolism ; Homocysteine ; Homocysteine - metabolism ; Humans ; Hyperhomocysteinemia ; Kidney diseases ; Laboratories ; Liver ; Liver - cytology ; Liver cirrhosis ; Liver diseases ; Lysine - metabolism ; Male ; Methylation ; Methyltransferases ; Mice ; Mice, Inbred C57BL ; Nephrology ; Promoter Regions, Genetic - genetics ; Proteins ; Regulatory sequences ; Repressor Proteins - metabolism ; Rodents ; siRNA ; Transcription factors</subject><ispartof>PloS one, 2015-07, Vol.10 (7), p.e0130421-e0130421</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Lei et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Lei et al 2015 Lei et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-b527c34dd817b4a31d3727c36a08c697cd9ad0ec1f35d0fd0281c80a07cc7fc93</citedby><cites>FETCH-LOGICAL-c692t-b527c34dd817b4a31d3727c36a08c697cd9ad0ec1f35d0fd0281c80a07cc7fc93</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/PMC4508059/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508059/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2100,2926,23864,27922,27923,53789,53791,79370,79371</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26192994$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Yang, Xiao-Feng</contributor><creatorcontrib>Lei, Wenjing</creatorcontrib><creatorcontrib>Long, Yanjun</creatorcontrib><creatorcontrib>Li, Shuang</creatorcontrib><creatorcontrib>Liu, Ze</creatorcontrib><creatorcontrib>Zhu, Fengxin</creatorcontrib><creatorcontrib>Hou, Fan Fan</creatorcontrib><creatorcontrib>Nie, Jing</creatorcontrib><title>Homocysteine Induces Collagen I Expression by Downregulating Histone Methyltransferase G9a</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Hyperhomocysteinemia (HHcy) leads to several clinical manifestations including hepatic fibrosis. Excess deposition of extracellular matrix (ECM) components including collagen is the eponymous lesion of liver fibrosis. In this study, we demonstrated that elevated concentration of Hcy induced the expression of collagen type I in cultured human liver cells as well as in liver tissue of HHcy mice. Meanwhile, Hcy inhibited the expression of histone methyltransferase G9a. Mechanistically, silencing endogenous G9a by siRNA enhanced the promoter activity of COL1A1 in LO2 cells. Conversely, overexpressing G9a inhibited the promoter activity of COL1A1. CHIP assay demonstrated that G9a binds to the neuron-restrictive silencer element (NRSE) on the promoter of COL1A1. Hcy treatment decreased the binding of G9a on NRSE, which in turn decreased the level of H3K9me2 on the promoter of COL1A1, led to upregulation of COL1A1. Taken together, these results provide a novel mechanism on explaining how HHcy promotes ECM production.</description><subject>Animals</subject><subject>Base Sequence</subject><subject>Cancer</subject><subject>Cell Line</subject><subject>Cocaine</subject><subject>Collagen</subject><subject>Collagen (type I)</subject><subject>Collagen Type I - genetics</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>Down-Regulation</subject><subject>Epigenetics</subject><subject>Extracellular matrix</subject><subject>Fibrosis</subject><subject>Gene expression</subject><subject>Hepatocytes</subject><subject>Histocompatibility Antigens - genetics</subject><subject>Histocompatibility Antigens - metabolism</subject><subject>Histone methyltransferase</subject><subject>Histone-Lysine N-Methyltransferase - genetics</subject><subject>Histone-Lysine N-Methyltransferase - metabolism</subject><subject>Histones</subject><subject>Histones - chemistry</subject><subject>Histones - metabolism</subject><subject>Homocysteine</subject><subject>Homocysteine - metabolism</subject><subject>Humans</subject><subject>Hyperhomocysteinemia</subject><subject>Kidney diseases</subject><subject>Laboratories</subject><subject>Liver</subject><subject>Liver - cytology</subject><subject>Liver cirrhosis</subject><subject>Liver diseases</subject><subject>Lysine - metabolism</subject><subject>Male</subject><subject>Methylation</subject><subject>Methyltransferases</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Nephrology</subject><subject>Promoter Regions, Genetic - genetics</subject><subject>Proteins</subject><subject>Regulatory sequences</subject><subject>Repressor Proteins - metabolism</subject><subject>Rodents</subject><subject>siRNA</subject><subject>Transcription factors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk11v0zAUhiMEYmPwDxBEQkJw0eKvJvEN0lTGWmloEl8X3FiO7aSuXLuznW399zhrNjVoF8gXsU6e9z0-xz5Z9hqCKcQl_LR2nbfcTLfOqimAGBAEn2THkGI0KRDATw_2R9mLENYAzHBVFM-zI1RAiiglx9mfhds4sQtRaavypZWdUCGfO2N4q2y-zM9ut16FoJ3N613-xd1Yr9rO8Khtmy90iCl9_k3F1c5Ez21olOdB5eeUv8yeNdwE9Wr4nmS_vp79nC8mF5fny_npxUQUFMVJPUOlwETKCpY14RhKXPaRgoMqEaWQlEugBGzwTIJGAlRBUQEOSiHKRlB8kr3d-26NC2xoS2AwaQlCBcKJWO4J6fiabb3ecL9jjmt2F3C-ZdxHLYxipCoxpqguGlCSAlQ1bpqq6ruFsSSkz_Z5yNbVGyWFsqlsMzId_7F6xVp3zcgMVGDWG3wYDLy76lSIbKODUKnhVrnu7twUAVRSktB3_6CPVzdQLU8FaNu4lFf0puw0IQQUkMBETR-h0pJqo0W6xEan-EjwcSRITFS3seVdCGz54_v_s5e_x-z7A3aluImr4EwX0xMLY5DsQeFdCF41D02GgPUjcN8N1o8AG0Ygyd4cXtCD6P7N479OJ__q</recordid><startdate>20150720</startdate><enddate>20150720</enddate><creator>Lei, Wenjing</creator><creator>Long, Yanjun</creator><creator>Li, Shuang</creator><creator>Liu, Ze</creator><creator>Zhu, Fengxin</creator><creator>Hou, Fan Fan</creator><creator>Nie, Jing</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150720</creationdate><title>Homocysteine Induces Collagen I Expression by Downregulating Histone Methyltransferase G9a</title><author>Lei, Wenjing ; Long, Yanjun ; Li, Shuang ; Liu, Ze ; Zhu, Fengxin ; Hou, Fan Fan ; Nie, Jing</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-b527c34dd817b4a31d3727c36a08c697cd9ad0ec1f35d0fd0281c80a07cc7fc93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Base Sequence</topic><topic>Cancer</topic><topic>Cell Line</topic><topic>Cocaine</topic><topic>Collagen</topic><topic>Collagen (type I)</topic><topic>Collagen Type I - genetics</topic><topic>Deoxyribonucleic acid</topic><topic>DNA</topic><topic>DNA methylation</topic><topic>Down-Regulation</topic><topic>Epigenetics</topic><topic>Extracellular matrix</topic><topic>Fibrosis</topic><topic>Gene expression</topic><topic>Hepatocytes</topic><topic>Histocompatibility Antigens - genetics</topic><topic>Histocompatibility Antigens - metabolism</topic><topic>Histone methyltransferase</topic><topic>Histone-Lysine N-Methyltransferase - genetics</topic><topic>Histone-Lysine N-Methyltransferase - metabolism</topic><topic>Histones</topic><topic>Histones - chemistry</topic><topic>Histones - metabolism</topic><topic>Homocysteine</topic><topic>Homocysteine - metabolism</topic><topic>Humans</topic><topic>Hyperhomocysteinemia</topic><topic>Kidney diseases</topic><topic>Laboratories</topic><topic>Liver</topic><topic>Liver - cytology</topic><topic>Liver cirrhosis</topic><topic>Liver diseases</topic><topic>Lysine - metabolism</topic><topic>Male</topic><topic>Methylation</topic><topic>Methyltransferases</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Nephrology</topic><topic>Promoter Regions, Genetic - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lei, Wenjing</au><au>Long, Yanjun</au><au>Li, Shuang</au><au>Liu, Ze</au><au>Zhu, Fengxin</au><au>Hou, Fan Fan</au><au>Nie, Jing</au><au>Yang, Xiao-Feng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Homocysteine Induces Collagen I Expression by Downregulating Histone Methyltransferase G9a</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-07-20</date><risdate>2015</risdate><volume>10</volume><issue>7</issue><spage>e0130421</spage><epage>e0130421</epage><pages>e0130421-e0130421</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Hyperhomocysteinemia (HHcy) leads to several clinical manifestations including hepatic fibrosis. Excess deposition of extracellular matrix (ECM) components including collagen is the eponymous lesion of liver fibrosis. In this study, we demonstrated that elevated concentration of Hcy induced the expression of collagen type I in cultured human liver cells as well as in liver tissue of HHcy mice. Meanwhile, Hcy inhibited the expression of histone methyltransferase G9a. Mechanistically, silencing endogenous G9a by siRNA enhanced the promoter activity of COL1A1 in LO2 cells. Conversely, overexpressing G9a inhibited the promoter activity of COL1A1. CHIP assay demonstrated that G9a binds to the neuron-restrictive silencer element (NRSE) on the promoter of COL1A1. Hcy treatment decreased the binding of G9a on NRSE, which in turn decreased the level of H3K9me2 on the promoter of COL1A1, led to upregulation of COL1A1. Taken together, these results provide a novel mechanism on explaining how HHcy promotes ECM production.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26192994</pmid><doi>10.1371/journal.pone.0130421</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Base Sequence Cancer Cell Line Cocaine Collagen Collagen (type I) Collagen Type I - genetics Deoxyribonucleic acid DNA DNA methylation Down-Regulation Epigenetics Extracellular matrix Fibrosis Gene expression Hepatocytes Histocompatibility Antigens - genetics Histocompatibility Antigens - metabolism Histone methyltransferase Histone-Lysine N-Methyltransferase - genetics Histone-Lysine N-Methyltransferase - metabolism Histones Histones - chemistry Histones - metabolism Homocysteine Homocysteine - metabolism Humans Hyperhomocysteinemia Kidney diseases Laboratories Liver Liver - cytology Liver cirrhosis Liver diseases Lysine - metabolism Male Methylation Methyltransferases Mice Mice, Inbred C57BL Nephrology Promoter Regions, Genetic - genetics Proteins Regulatory sequences Repressor Proteins - metabolism Rodents siRNA Transcription factors |
| title | Homocysteine Induces Collagen I Expression by Downregulating Histone Methyltransferase G9a |
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