RNF12 initiates X-chromosome inactivation by targeting REX1 for degradation
The pluripotency factor REX1 is a key target of RNF12 during X-chromosome inactivation; degradation of REX1 by RNF12 leads to relief of its inhibitory action on X-chromosome inactivation. X-chromosome inactivation by RNF12 In placental mammals, X-linked gene dosage compensation between XY males and...
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| Veröffentlicht in: | Nature (London) 2012-05, Vol.485 (7398), p.386-390 |
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| creator | Gontan, Cristina Achame, Eskeatnaf Mulugeta Demmers, Jeroen Barakat, Tahsin Stefan Rentmeester, Eveline van IJcken, Wilfred Grootegoed, J. Anton Gribnau, Joost |
| description | The pluripotency factor REX1 is a key target of RNF12 during X-chromosome inactivation; degradation of REX1 by RNF12 leads to relief of its inhibitory action on X-chromosome inactivation.
X-chromosome inactivation by RNF12
In placental mammals, X-linked gene dosage compensation between XY males and XX females is achieved by random inactivation of one X chromosome in female somatic cells. The E3 ubiquitin ligase RNF12 is required for initiation of X-chromosome inactivation (XCI) in embryonic stem cells, but its downstream targets have been unclear. Here, Gribnau and colleagues demonstrate that the pluripotency factor REX1 is a key target of RNF12 during XCI. RNF12 degradation of REX1 leads to relief of its inhibitory action on XCI.
Evolution of the mammalian sex chromosomes has resulted in a heterologous X and Y pair, where the Y chromosome has lost most of its genes. Hence, there is a need for X-linked gene dosage compensation between XY males and XX females. In placental mammals, this is achieved by random inactivation of one X chromosome in all female somatic cells
1
. Upregulation of
Xist
transcription on the future inactive X chromosome acts against
Tsix
antisense transcription, and spreading of
Xist
RNA in
cis
triggers epigenetic changes leading to X-chromosome inactivation. Previously, we have shown that the X-encoded E3 ubiquitin ligase RNF12 is upregulated in differentiating mouse embryonic stem cells and activates
Xist
transcription and X-chromosome inactivation
2
. Here we identify the pluripotency factor REX1 as a key target of RNF12 in the mechanism of X-chromosome inactivation. RNF12 causes ubiquitination and proteasomal degradation of REX1, and
Rnf12
knockout embryonic stem cells show an increased level of REX1. Using chromatin immunoprecipitation sequencing, REX1 binding sites were detected in
Xist
and
Tsix
regulatory regions. Overexpression of REX1 in female embryonic stem cells was found to inhibit
Xist
transcription and X-chromosome inactivation, whereas male
Rex1
+/−
embryonic stem cells showed ectopic X-chromosome inactivation. From this, we propose that RNF12 causes REX1 breakdown through dose-dependent catalysis, thereby representing an important pathway to initiate X-chromosome inactivation.
Rex1
and
Xist
are present only in placental mammals, which points to co-evolution of these two genes and X-chromosome inactivation. |
| doi_str_mv | 10.1038/nature11070 |
| format | Article |
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X-chromosome inactivation by RNF12
In placental mammals, X-linked gene dosage compensation between XY males and XX females is achieved by random inactivation of one X chromosome in female somatic cells. The E3 ubiquitin ligase RNF12 is required for initiation of X-chromosome inactivation (XCI) in embryonic stem cells, but its downstream targets have been unclear. Here, Gribnau and colleagues demonstrate that the pluripotency factor REX1 is a key target of RNF12 during XCI. RNF12 degradation of REX1 leads to relief of its inhibitory action on XCI.
Evolution of the mammalian sex chromosomes has resulted in a heterologous X and Y pair, where the Y chromosome has lost most of its genes. Hence, there is a need for X-linked gene dosage compensation between XY males and XX females. In placental mammals, this is achieved by random inactivation of one X chromosome in all female somatic cells
1
. Upregulation of
Xist
transcription on the future inactive X chromosome acts against
Tsix
antisense transcription, and spreading of
Xist
RNA in
cis
triggers epigenetic changes leading to X-chromosome inactivation. Previously, we have shown that the X-encoded E3 ubiquitin ligase RNF12 is upregulated in differentiating mouse embryonic stem cells and activates
Xist
transcription and X-chromosome inactivation
2
. Here we identify the pluripotency factor REX1 as a key target of RNF12 in the mechanism of X-chromosome inactivation. RNF12 causes ubiquitination and proteasomal degradation of REX1, and
Rnf12
knockout embryonic stem cells show an increased level of REX1. Using chromatin immunoprecipitation sequencing, REX1 binding sites were detected in
Xist
and
Tsix
regulatory regions. Overexpression of REX1 in female embryonic stem cells was found to inhibit
Xist
transcription and X-chromosome inactivation, whereas male
Rex1
+/−
embryonic stem cells showed ectopic X-chromosome inactivation. From this, we propose that RNF12 causes REX1 breakdown through dose-dependent catalysis, thereby representing an important pathway to initiate X-chromosome inactivation.
Rex1
and
Xist
are present only in placental mammals, which points to co-evolution of these two genes and X-chromosome inactivation.</description><identifier>ISSN: 0028-0836</identifier><identifier>EISSN: 1476-4687</identifier><identifier>DOI: 10.1038/nature11070</identifier><identifier>PMID: 22596162</identifier><identifier>CODEN: NATUAS</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/136 ; 631/181/2474 ; 631/208/212/177 ; 631/337/103 ; Amino Acid Sequence ; Analytical, structural and metabolic biochemistry ; Animals ; Binding Sites ; Biological and medical sciences ; Catalysis ; Chromosomes ; Embryonic stem cells ; Embryonic Stem Cells - metabolism ; Evolution ; Female ; Fundamental and applied biological sciences. Psychology ; Gene Expression Regulation ; Genetic aspects ; Genetic transcription ; Genetics ; Humanities and Social Sciences ; Inactivation ; letter ; Ligases ; Male ; Mammals ; Mass spectrometry ; Mice ; Molecular and cellular biology ; Molecular Sequence Data ; multidisciplinary ; Physiological aspects ; Proteasome Endopeptidase Complex - metabolism ; Protein Binding ; Proteins ; RNA, Long Noncoding ; RNA, Untranslated - genetics ; Science ; Science (multidisciplinary) ; Stem cells ; Transcription Factors - deficiency ; Transcription Factors - genetics ; Transcription Factors - metabolism ; Transcription, Genetic ; Ubiquitin-Protein Ligases - genetics ; Ubiquitin-Protein Ligases - metabolism ; Ubiquitination ; X chromosome ; X Chromosome - genetics ; X Chromosome Inactivation</subject><ispartof>Nature (London), 2012-05, Vol.485 (7398), p.386-390</ispartof><rights>Springer Nature Limited 2012</rights><rights>2014 INIST-CNRS</rights><rights>COPYRIGHT 2012 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group May 17, 2012</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c616t-a787885d121f773fc00d8fa2056b2e4f380117b4b878b8e52c87ac1f14d450683</citedby><cites>FETCH-LOGICAL-c616t-a787885d121f773fc00d8fa2056b2e4f380117b4b878b8e52c87ac1f14d450683</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nature11070$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nature11070$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25883913$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22596162$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Gontan, Cristina</creatorcontrib><creatorcontrib>Achame, Eskeatnaf Mulugeta</creatorcontrib><creatorcontrib>Demmers, Jeroen</creatorcontrib><creatorcontrib>Barakat, Tahsin Stefan</creatorcontrib><creatorcontrib>Rentmeester, Eveline</creatorcontrib><creatorcontrib>van IJcken, Wilfred</creatorcontrib><creatorcontrib>Grootegoed, J. Anton</creatorcontrib><creatorcontrib>Gribnau, Joost</creatorcontrib><title>RNF12 initiates X-chromosome inactivation by targeting REX1 for degradation</title><title>Nature (London)</title><addtitle>Nature</addtitle><addtitle>Nature</addtitle><description>The pluripotency factor REX1 is a key target of RNF12 during X-chromosome inactivation; degradation of REX1 by RNF12 leads to relief of its inhibitory action on X-chromosome inactivation.
X-chromosome inactivation by RNF12
In placental mammals, X-linked gene dosage compensation between XY males and XX females is achieved by random inactivation of one X chromosome in female somatic cells. The E3 ubiquitin ligase RNF12 is required for initiation of X-chromosome inactivation (XCI) in embryonic stem cells, but its downstream targets have been unclear. Here, Gribnau and colleagues demonstrate that the pluripotency factor REX1 is a key target of RNF12 during XCI. RNF12 degradation of REX1 leads to relief of its inhibitory action on XCI.
Evolution of the mammalian sex chromosomes has resulted in a heterologous X and Y pair, where the Y chromosome has lost most of its genes. Hence, there is a need for X-linked gene dosage compensation between XY males and XX females. In placental mammals, this is achieved by random inactivation of one X chromosome in all female somatic cells
1
. Upregulation of
Xist
transcription on the future inactive X chromosome acts against
Tsix
antisense transcription, and spreading of
Xist
RNA in
cis
triggers epigenetic changes leading to X-chromosome inactivation. Previously, we have shown that the X-encoded E3 ubiquitin ligase RNF12 is upregulated in differentiating mouse embryonic stem cells and activates
Xist
transcription and X-chromosome inactivation
2
. Here we identify the pluripotency factor REX1 as a key target of RNF12 in the mechanism of X-chromosome inactivation. RNF12 causes ubiquitination and proteasomal degradation of REX1, and
Rnf12
knockout embryonic stem cells show an increased level of REX1. Using chromatin immunoprecipitation sequencing, REX1 binding sites were detected in
Xist
and
Tsix
regulatory regions. Overexpression of REX1 in female embryonic stem cells was found to inhibit
Xist
transcription and X-chromosome inactivation, whereas male
Rex1
+/−
embryonic stem cells showed ectopic X-chromosome inactivation. From this, we propose that RNF12 causes REX1 breakdown through dose-dependent catalysis, thereby representing an important pathway to initiate X-chromosome inactivation.
Rex1
and
Xist
are present only in placental mammals, which points to co-evolution of these two genes and X-chromosome inactivation.</description><subject>631/136</subject><subject>631/181/2474</subject><subject>631/208/212/177</subject><subject>631/337/103</subject><subject>Amino Acid Sequence</subject><subject>Analytical, structural and metabolic biochemistry</subject><subject>Animals</subject><subject>Binding Sites</subject><subject>Biological and medical sciences</subject><subject>Catalysis</subject><subject>Chromosomes</subject><subject>Embryonic stem cells</subject><subject>Embryonic Stem Cells - metabolism</subject><subject>Evolution</subject><subject>Female</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene Expression Regulation</subject><subject>Genetic aspects</subject><subject>Genetic transcription</subject><subject>Genetics</subject><subject>Humanities and Social Sciences</subject><subject>Inactivation</subject><subject>letter</subject><subject>Ligases</subject><subject>Male</subject><subject>Mammals</subject><subject>Mass spectrometry</subject><subject>Mice</subject><subject>Molecular and cellular biology</subject><subject>Molecular Sequence Data</subject><subject>multidisciplinary</subject><subject>Physiological aspects</subject><subject>Proteasome Endopeptidase Complex - metabolism</subject><subject>Protein Binding</subject><subject>Proteins</subject><subject>RNA, Long Noncoding</subject><subject>RNA, Untranslated - genetics</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Stem cells</subject><subject>Transcription Factors - deficiency</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>Transcription, Genetic</subject><subject>Ubiquitin-Protein Ligases - genetics</subject><subject>Ubiquitin-Protein Ligases - metabolism</subject><subject>Ubiquitination</subject><subject>X chromosome</subject><subject>X Chromosome - genetics</subject><subject>X Chromosome Inactivation</subject><issn>0028-0836</issn><issn>1476-4687</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpt0t1rFDEQAPAgij2rT77LogiKbs1kP5J7LKXVYlE4Ffq2ZLOTNWU3uSZZaf_75rzT3umRh8Dkl5lkGEKeAz0CWogPVsbJIwDl9AGZQcnrvKwFf0hmlDKRU1HUB-RJCFeU0gp4-ZgcMFbNa6jZjHxefDkDlhlropERQ3aZq5_ejS64EVNYqmh-yWiczdrbLErfYzS2zxanl5Bp57MOey-73-IpeaTlEPDZZj8kP85Ov598yi--fjw_Ob7IVaoZc8kFF6LqgIHmvNCK0k5oyWhVtwxLXQgKwNuyTawVWDEluFSgoezKitaiOCRv1nmX3l1PGGIzmqBwGKRFN4UGKFR0zutiRV_9Q6_c5G163UrxmjJawr3q5YCNsdpFL9UqaXPM5owKAdU8qXyP6tGil4OzqE0K7_iXe7xamutmGx3tQWl1OBq1N-vbnQvJRLyJvZxCaM6_LXbtu7VV3oXgUTdLb0bpb9Pnm9XsNFuzk_SLTa-mdsTur_0zLAm83gAZlBy0l1aZcO8qIYo5FMm9X7uQjmyPfrvp_9e9A6dq1Uw</recordid><startdate>20120517</startdate><enddate>20120517</enddate><creator>Gontan, Cristina</creator><creator>Achame, Eskeatnaf Mulugeta</creator><creator>Demmers, Jeroen</creator><creator>Barakat, Tahsin Stefan</creator><creator>Rentmeester, Eveline</creator><creator>van IJcken, Wilfred</creator><creator>Grootegoed, J. 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Psychology</topic><topic>Gene Expression Regulation</topic><topic>Genetic aspects</topic><topic>Genetic transcription</topic><topic>Genetics</topic><topic>Humanities and Social Sciences</topic><topic>Inactivation</topic><topic>letter</topic><topic>Ligases</topic><topic>Male</topic><topic>Mammals</topic><topic>Mass spectrometry</topic><topic>Mice</topic><topic>Molecular and cellular biology</topic><topic>Molecular Sequence Data</topic><topic>multidisciplinary</topic><topic>Physiological aspects</topic><topic>Proteasome Endopeptidase Complex - metabolism</topic><topic>Protein Binding</topic><topic>Proteins</topic><topic>RNA, Long Noncoding</topic><topic>RNA, Untranslated - genetics</topic><topic>Science</topic><topic>Science (multidisciplinary)</topic><topic>Stem cells</topic><topic>Transcription Factors - deficiency</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>Transcription, Genetic</topic><topic>Ubiquitin-Protein Ligases - genetics</topic><topic>Ubiquitin-Protein Ligases - metabolism</topic><topic>Ubiquitination</topic><topic>X chromosome</topic><topic>X Chromosome - genetics</topic><topic>X Chromosome Inactivation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gontan, Cristina</creatorcontrib><creatorcontrib>Achame, Eskeatnaf Mulugeta</creatorcontrib><creatorcontrib>Demmers, Jeroen</creatorcontrib><creatorcontrib>Barakat, Tahsin Stefan</creatorcontrib><creatorcontrib>Rentmeester, Eveline</creatorcontrib><creatorcontrib>van IJcken, Wilfred</creatorcontrib><creatorcontrib>Grootegoed, J. 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Anton</au><au>Gribnau, Joost</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>RNF12 initiates X-chromosome inactivation by targeting REX1 for degradation</atitle><jtitle>Nature (London)</jtitle><stitle>Nature</stitle><addtitle>Nature</addtitle><date>2012-05-17</date><risdate>2012</risdate><volume>485</volume><issue>7398</issue><spage>386</spage><epage>390</epage><pages>386-390</pages><issn>0028-0836</issn><eissn>1476-4687</eissn><coden>NATUAS</coden><abstract>The pluripotency factor REX1 is a key target of RNF12 during X-chromosome inactivation; degradation of REX1 by RNF12 leads to relief of its inhibitory action on X-chromosome inactivation.
X-chromosome inactivation by RNF12
In placental mammals, X-linked gene dosage compensation between XY males and XX females is achieved by random inactivation of one X chromosome in female somatic cells. The E3 ubiquitin ligase RNF12 is required for initiation of X-chromosome inactivation (XCI) in embryonic stem cells, but its downstream targets have been unclear. Here, Gribnau and colleagues demonstrate that the pluripotency factor REX1 is a key target of RNF12 during XCI. RNF12 degradation of REX1 leads to relief of its inhibitory action on XCI.
Evolution of the mammalian sex chromosomes has resulted in a heterologous X and Y pair, where the Y chromosome has lost most of its genes. Hence, there is a need for X-linked gene dosage compensation between XY males and XX females. In placental mammals, this is achieved by random inactivation of one X chromosome in all female somatic cells
1
. Upregulation of
Xist
transcription on the future inactive X chromosome acts against
Tsix
antisense transcription, and spreading of
Xist
RNA in
cis
triggers epigenetic changes leading to X-chromosome inactivation. Previously, we have shown that the X-encoded E3 ubiquitin ligase RNF12 is upregulated in differentiating mouse embryonic stem cells and activates
Xist
transcription and X-chromosome inactivation
2
. Here we identify the pluripotency factor REX1 as a key target of RNF12 in the mechanism of X-chromosome inactivation. RNF12 causes ubiquitination and proteasomal degradation of REX1, and
Rnf12
knockout embryonic stem cells show an increased level of REX1. Using chromatin immunoprecipitation sequencing, REX1 binding sites were detected in
Xist
and
Tsix
regulatory regions. Overexpression of REX1 in female embryonic stem cells was found to inhibit
Xist
transcription and X-chromosome inactivation, whereas male
Rex1
+/−
embryonic stem cells showed ectopic X-chromosome inactivation. From this, we propose that RNF12 causes REX1 breakdown through dose-dependent catalysis, thereby representing an important pathway to initiate X-chromosome inactivation.
Rex1
and
Xist
are present only in placental mammals, which points to co-evolution of these two genes and X-chromosome inactivation.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>22596162</pmid><doi>10.1038/nature11070</doi><tpages>5</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0028-0836 |
| ispartof | Nature (London), 2012-05, Vol.485 (7398), p.386-390 |
| issn | 0028-0836 1476-4687 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1015097638 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature |
| subjects | 631/136 631/181/2474 631/208/212/177 631/337/103 Amino Acid Sequence Analytical, structural and metabolic biochemistry Animals Binding Sites Biological and medical sciences Catalysis Chromosomes Embryonic stem cells Embryonic Stem Cells - metabolism Evolution Female Fundamental and applied biological sciences. Psychology Gene Expression Regulation Genetic aspects Genetic transcription Genetics Humanities and Social Sciences Inactivation letter Ligases Male Mammals Mass spectrometry Mice Molecular and cellular biology Molecular Sequence Data multidisciplinary Physiological aspects Proteasome Endopeptidase Complex - metabolism Protein Binding Proteins RNA, Long Noncoding RNA, Untranslated - genetics Science Science (multidisciplinary) Stem cells Transcription Factors - deficiency Transcription Factors - genetics Transcription Factors - metabolism Transcription, Genetic Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism Ubiquitination X chromosome X Chromosome - genetics X Chromosome Inactivation |
| title | RNF12 initiates X-chromosome inactivation by targeting REX1 for degradation |
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