OCT4 establishes and maintains nucleosome-depleted regions that provide additional layers of epigenetic regulation of its target genes
Recent epigenome-wide mapping studies describe nucleosome-depleted regions (NDRs) at transcription start sites and enhancers. However, these static maps do not address causality or the roles of NDRs in gene control, and their relationship to transcription factors and DNA methylation is not well unde...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2011-08, Vol.108 (35), p.14497-14502 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | You, Jueng Soo Kelly, Theresa K De Carvalho, Daniel D Taberlay, Phillippa C Liang, Gangning Jones, Peter A |
| description | Recent epigenome-wide mapping studies describe nucleosome-depleted regions (NDRs) at transcription start sites and enhancers. However, these static maps do not address causality or the roles of NDRs in gene control, and their relationship to transcription factors and DNA methylation is not well understood. Using a high-resolution single-molecule mapping approach to simultaneously investigate endogenous DNA methylation and nucleosome occupancies on individual DNA molecules, we show that the unmethylated OCT4 distal enhancer has an NDR, whereas NANOG has a clear NDR at its proximal promoter. These NDRs are maintained by binding of OCT4 and are required for OCT4 and NANOG expression. Differentiation causes a rapid loss of both NDRs accompanied by nucleosome occupancy, which precedes de novo DNA methylation. NDRs can be restored by forced expression of OCT4 in somatic cells but only when there is no cytosine methylation. These data show the central role of the NDRs, established by OCT4, in ensuring the autoregulatory loop of pluripotency and, furthermore, that de novo methylation follows the loss of NDRs and stabilizes the suppressed state. |
| doi_str_mv | 10.1073/pnas.1111309108 |
| format | Article |
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However, these static maps do not address causality or the roles of NDRs in gene control, and their relationship to transcription factors and DNA methylation is not well understood. Using a high-resolution single-molecule mapping approach to simultaneously investigate endogenous DNA methylation and nucleosome occupancies on individual DNA molecules, we show that the unmethylated OCT4 distal enhancer has an NDR, whereas NANOG has a clear NDR at its proximal promoter. These NDRs are maintained by binding of OCT4 and are required for OCT4 and NANOG expression. Differentiation causes a rapid loss of both NDRs accompanied by nucleosome occupancy, which precedes de novo DNA methylation. NDRs can be restored by forced expression of OCT4 in somatic cells but only when there is no cytosine methylation. These data show the central role of the NDRs, established by OCT4, in ensuring the autoregulatory loop of pluripotency and, furthermore, that de novo methylation follows the loss of NDRs and stabilizes the suppressed state.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1111309108</identifier><identifier>PMID: 21844352</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Biological Sciences ; Cell Differentiation ; Cell lines ; Cells ; Cells, Cultured ; CpG Islands ; Cytosine ; Data processing ; Differentiation ; DNA ; DNA Methylation ; Embryonic stem cells ; Enhancers ; Epigenesis, Genetic ; Epigenetics ; Gene Expression Regulation ; Gene mapping ; Genes ; Genomics ; HCT116 cells ; Homeodomain Proteins - physiology ; Humans ; Methylation ; Nanog Homeobox Protein ; Nucleosomes ; Nucleosomes - physiology ; Oct-4 protein ; Octamer Transcription Factor-3 - physiology ; Pluripotent stem cells ; Promoters ; Somatic cells ; Stem cells ; Transcription factors</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2011-08, Vol.108 (35), p.14497-14502</ispartof><rights>copyright © 1993–2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Aug 30, 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c555t-8b4bf6f2310e9d8f1eb32209f740cbd75f7fce168cde35dea6084eac77a731053</citedby><cites>FETCH-LOGICAL-c555t-8b4bf6f2310e9d8f1eb32209f740cbd75f7fce168cde35dea6084eac77a731053</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/108/35.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/27979320$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/27979320$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,723,776,780,799,881,27903,27904,53770,53772,57996,58229</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21844352$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>You, Jueng Soo</creatorcontrib><creatorcontrib>Kelly, Theresa K</creatorcontrib><creatorcontrib>De Carvalho, Daniel D</creatorcontrib><creatorcontrib>Taberlay, Phillippa C</creatorcontrib><creatorcontrib>Liang, Gangning</creatorcontrib><creatorcontrib>Jones, Peter A</creatorcontrib><title>OCT4 establishes and maintains nucleosome-depleted regions that provide additional layers of epigenetic regulation of its target genes</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Recent epigenome-wide mapping studies describe nucleosome-depleted regions (NDRs) at transcription start sites and enhancers. However, these static maps do not address causality or the roles of NDRs in gene control, and their relationship to transcription factors and DNA methylation is not well understood. Using a high-resolution single-molecule mapping approach to simultaneously investigate endogenous DNA methylation and nucleosome occupancies on individual DNA molecules, we show that the unmethylated OCT4 distal enhancer has an NDR, whereas NANOG has a clear NDR at its proximal promoter. These NDRs are maintained by binding of OCT4 and are required for OCT4 and NANOG expression. Differentiation causes a rapid loss of both NDRs accompanied by nucleosome occupancy, which precedes de novo DNA methylation. NDRs can be restored by forced expression of OCT4 in somatic cells but only when there is no cytosine methylation. 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However, these static maps do not address causality or the roles of NDRs in gene control, and their relationship to transcription factors and DNA methylation is not well understood. Using a high-resolution single-molecule mapping approach to simultaneously investigate endogenous DNA methylation and nucleosome occupancies on individual DNA molecules, we show that the unmethylated OCT4 distal enhancer has an NDR, whereas NANOG has a clear NDR at its proximal promoter. These NDRs are maintained by binding of OCT4 and are required for OCT4 and NANOG expression. Differentiation causes a rapid loss of both NDRs accompanied by nucleosome occupancy, which precedes de novo DNA methylation. NDRs can be restored by forced expression of OCT4 in somatic cells but only when there is no cytosine methylation. 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| subjects | Biological Sciences Cell Differentiation Cell lines Cells Cells, Cultured CpG Islands Cytosine Data processing Differentiation DNA DNA Methylation Embryonic stem cells Enhancers Epigenesis, Genetic Epigenetics Gene Expression Regulation Gene mapping Genes Genomics HCT116 cells Homeodomain Proteins - physiology Humans Methylation Nanog Homeobox Protein Nucleosomes Nucleosomes - physiology Oct-4 protein Octamer Transcription Factor-3 - physiology Pluripotent stem cells Promoters Somatic cells Stem cells Transcription factors |
| title | OCT4 establishes and maintains nucleosome-depleted regions that provide additional layers of epigenetic regulation of its target genes |
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