A disproportionate impact of G9a methyltransferase deficiency on the X chromosome
G9a is a histone methyltransferase responsible for the dimethylation of histone H3 at lysine 9 (H3K9me2). G9a plays key roles in transcriptional silencing of developmentally regulated genes, but its role in X-chromosome inactivation (XCI) has been under debate. Here, we uncover a female-specific fun...
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| Veröffentlicht in: | Genes & development 2021-07, Vol.35 (13-14), p.1035-1054 |
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| container_issue | 13-14 |
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| container_title | Genes & development |
| container_volume | 35 |
| creator | Szanto, Attila Aguilar, Rodrigo Kesner, Barry Blum, Roy Wang, Danni Cifuentes-Rojas, Catherine Del Rosario, Brian C Kis-Toth, Katalin Lee, Jeannie T |
| description | G9a is a histone methyltransferase responsible for the dimethylation of histone H3 at lysine 9 (H3K9me2). G9a plays key roles in transcriptional silencing of developmentally regulated genes, but its role in X-chromosome inactivation (XCI) has been under debate. Here, we uncover a female-specific function of G9a and demonstrate that deleting G9a has a disproportionate impact on the X chromosome relative to the rest of the genome. G9a deficiency causes a failure of XCI and female-specific hypersensitivity to drug inhibition of H3K9me2. We show that G9a interacts with Tsix and Xist RNAs, and that competitive inhibition of the G9a-RNA interaction recapitulates the XCI defect. During XCI, Xist recruits G9a to silence X-linked genes on the future inactive X. In parallel on the future Xa, Tsix recruits G9a to silence
in
Thus, RNA tethers G9a for allele-specific targeting of the H3K9me2 modification and the G9a-RNA interaction is essential for XCI. |
| doi_str_mv | 10.1101/gad.337592.120 |
| format | Article |
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in
Thus, RNA tethers G9a for allele-specific targeting of the H3K9me2 modification and the G9a-RNA interaction is essential for XCI.</description><identifier>ISSN: 0890-9369</identifier><identifier>EISSN: 1549-5477</identifier><identifier>DOI: 10.1101/gad.337592.120</identifier><identifier>PMID: 34168040</identifier><language>eng</language><publisher>United States: Cold Spring Harbor Laboratory Press</publisher><subject>Chromosomes, Human, X ; Female ; Histocompatibility Antigens - metabolism ; Histone-Lysine N-Methyltransferase - metabolism ; Histones - metabolism ; Humans ; Methyltransferases - genetics ; Research Paper ; RNA, Long Noncoding - genetics ; X Chromosome Inactivation - genetics</subject><ispartof>Genes & development, 2021-07, Vol.35 (13-14), p.1035-1054</ispartof><rights>2021 Szanto et al.; Published by Cold Spring Harbor Laboratory Press.</rights><rights>2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c390t-360a5caf43fefd3da56d011ff8ba728fe17f237817e349be359949dd6b5f1a973</citedby><cites>FETCH-LOGICAL-c390t-360a5caf43fefd3da56d011ff8ba728fe17f237817e349be359949dd6b5f1a973</cites><orcidid>0000-0003-0410-5478</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/PMC8247598/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247598/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34168040$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Szanto, Attila</creatorcontrib><creatorcontrib>Aguilar, Rodrigo</creatorcontrib><creatorcontrib>Kesner, Barry</creatorcontrib><creatorcontrib>Blum, Roy</creatorcontrib><creatorcontrib>Wang, Danni</creatorcontrib><creatorcontrib>Cifuentes-Rojas, Catherine</creatorcontrib><creatorcontrib>Del Rosario, Brian C</creatorcontrib><creatorcontrib>Kis-Toth, Katalin</creatorcontrib><creatorcontrib>Lee, Jeannie T</creatorcontrib><title>A disproportionate impact of G9a methyltransferase deficiency on the X chromosome</title><title>Genes & development</title><addtitle>Genes Dev</addtitle><description>G9a is a histone methyltransferase responsible for the dimethylation of histone H3 at lysine 9 (H3K9me2). G9a plays key roles in transcriptional silencing of developmentally regulated genes, but its role in X-chromosome inactivation (XCI) has been under debate. Here, we uncover a female-specific function of G9a and demonstrate that deleting G9a has a disproportionate impact on the X chromosome relative to the rest of the genome. G9a deficiency causes a failure of XCI and female-specific hypersensitivity to drug inhibition of H3K9me2. We show that G9a interacts with Tsix and Xist RNAs, and that competitive inhibition of the G9a-RNA interaction recapitulates the XCI defect. During XCI, Xist recruits G9a to silence X-linked genes on the future inactive X. In parallel on the future Xa, Tsix recruits G9a to silence
in
Thus, RNA tethers G9a for allele-specific targeting of the H3K9me2 modification and the G9a-RNA interaction is essential for XCI.</description><subject>Chromosomes, Human, X</subject><subject>Female</subject><subject>Histocompatibility Antigens - metabolism</subject><subject>Histone-Lysine N-Methyltransferase - metabolism</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Methyltransferases - genetics</subject><subject>Research Paper</subject><subject>RNA, Long Noncoding - genetics</subject><subject>X Chromosome Inactivation - genetics</subject><issn>0890-9369</issn><issn>1549-5477</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkUtLBDEQhIMouj6uHiVHL7Mmk9fkIoj4AkEEBW8hm3TcyMxkTGaF_feOrIqe-tDdVUV9CB1TMqeU0LNX6-eMKaHrOa3JFppRwXUluFLbaEYaTSrNpN5D-6W8EUIkkXIX7TFOZUM4maHHC-xjGXIaUh5j6u0IOHaDdSNOAd9oizsYl-t2zLYvAbItgD2E6CL0bo1Tj8cl4Bfsljl1qaQODtFOsG2Bo-95gJ6vr54ub6v7h5u7y4v7yjFNxopJYoWzgbMAwTNvhfSE0hCahVV1E4CqUDPVUAWM6wUwoTXX3suFCNRqxQ7Q-UZ3WC068A76KWNrhhw7m9cm2Wj-b_q4NK_pwzQ1n_pqJoHTb4Gc3ldQRtPF4qBtbQ9pVUwtuJBEUfXlNd-cupxKyRB-bSgxXxzMxMFsOJiJw_Rw8jfc7_lP8ewTXauF1A</recordid><startdate>20210701</startdate><enddate>20210701</enddate><creator>Szanto, Attila</creator><creator>Aguilar, Rodrigo</creator><creator>Kesner, Barry</creator><creator>Blum, Roy</creator><creator>Wang, Danni</creator><creator>Cifuentes-Rojas, Catherine</creator><creator>Del Rosario, Brian C</creator><creator>Kis-Toth, Katalin</creator><creator>Lee, Jeannie T</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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-0410-5478</orcidid></search><sort><creationdate>20210701</creationdate><title>A disproportionate impact of G9a methyltransferase deficiency on the X chromosome</title><author>Szanto, Attila ; Aguilar, Rodrigo ; Kesner, Barry ; Blum, Roy ; Wang, Danni ; Cifuentes-Rojas, Catherine ; Del Rosario, Brian C ; Kis-Toth, Katalin ; Lee, Jeannie T</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c390t-360a5caf43fefd3da56d011ff8ba728fe17f237817e349be359949dd6b5f1a973</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Chromosomes, Human, X</topic><topic>Female</topic><topic>Histocompatibility Antigens - metabolism</topic><topic>Histone-Lysine N-Methyltransferase - metabolism</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>Methyltransferases - genetics</topic><topic>Research Paper</topic><topic>RNA, Long Noncoding - genetics</topic><topic>X Chromosome Inactivation - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Szanto, Attila</creatorcontrib><creatorcontrib>Aguilar, Rodrigo</creatorcontrib><creatorcontrib>Kesner, Barry</creatorcontrib><creatorcontrib>Blum, Roy</creatorcontrib><creatorcontrib>Wang, Danni</creatorcontrib><creatorcontrib>Cifuentes-Rojas, Catherine</creatorcontrib><creatorcontrib>Del Rosario, Brian C</creatorcontrib><creatorcontrib>Kis-Toth, Katalin</creatorcontrib><creatorcontrib>Lee, Jeannie T</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Genes & development</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Szanto, Attila</au><au>Aguilar, Rodrigo</au><au>Kesner, Barry</au><au>Blum, Roy</au><au>Wang, Danni</au><au>Cifuentes-Rojas, Catherine</au><au>Del Rosario, Brian C</au><au>Kis-Toth, Katalin</au><au>Lee, Jeannie T</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A disproportionate impact of G9a methyltransferase deficiency on the X chromosome</atitle><jtitle>Genes & development</jtitle><addtitle>Genes Dev</addtitle><date>2021-07-01</date><risdate>2021</risdate><volume>35</volume><issue>13-14</issue><spage>1035</spage><epage>1054</epage><pages>1035-1054</pages><issn>0890-9369</issn><eissn>1549-5477</eissn><abstract>G9a is a histone methyltransferase responsible for the dimethylation of histone H3 at lysine 9 (H3K9me2). G9a plays key roles in transcriptional silencing of developmentally regulated genes, but its role in X-chromosome inactivation (XCI) has been under debate. Here, we uncover a female-specific function of G9a and demonstrate that deleting G9a has a disproportionate impact on the X chromosome relative to the rest of the genome. G9a deficiency causes a failure of XCI and female-specific hypersensitivity to drug inhibition of H3K9me2. We show that G9a interacts with Tsix and Xist RNAs, and that competitive inhibition of the G9a-RNA interaction recapitulates the XCI defect. During XCI, Xist recruits G9a to silence X-linked genes on the future inactive X. In parallel on the future Xa, Tsix recruits G9a to silence
in
Thus, RNA tethers G9a for allele-specific targeting of the H3K9me2 modification and the G9a-RNA interaction is essential for XCI.</abstract><cop>United States</cop><pub>Cold Spring Harbor Laboratory Press</pub><pmid>34168040</pmid><doi>10.1101/gad.337592.120</doi><tpages>20</tpages><orcidid>https://orcid.org/0000-0003-0410-5478</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Chromosomes, Human, X Female Histocompatibility Antigens - metabolism Histone-Lysine N-Methyltransferase - metabolism Histones - metabolism Humans Methyltransferases - genetics Research Paper RNA, Long Noncoding - genetics X Chromosome Inactivation - genetics |
| title | A disproportionate impact of G9a methyltransferase deficiency on the X chromosome |
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