Orphan CpG islands amplify poised enhancer regulatory activity and determine target gene responsiveness
CpG islands (CGIs) represent a widespread feature of vertebrate genomes, being associated with ~70% of all gene promoters. CGIs control transcription initiation by conferring nearby promoters with unique chromatin properties. In addition, there are thousands of distal or orphan CGIs (oCGIs) whose fu...
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| Veröffentlicht in: | Nature genetics 2021-07, Vol.53 (7), p.1036-1049 |
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| creator | Pachano, Tomas Sánchez-Gaya, Víctor Ealo, Thais Mariner-Faulí, Maria Bleckwehl, Tore Asenjo, Helena G. Respuela, Patricia Cruz-Molina, Sara Muñoz-San Martín, María Haro, Endika van IJcken, Wilfred F. J. Landeira, David Rada-Iglesias, Alvaro |
| description | CpG islands (CGIs) represent a widespread feature of vertebrate genomes, being associated with ~70% of all gene promoters. CGIs control transcription initiation by conferring nearby promoters with unique chromatin properties. In addition, there are thousands of distal or orphan CGIs (oCGIs) whose functional relevance is barely known. Here we show that oCGIs are an essential component of poised enhancers that augment their long-range regulatory activity and control the responsiveness of their target genes. Using a knock-in strategy in mouse embryonic stem cells, we introduced poised enhancers with or without oCGIs within topologically associating domains harboring genes with different types of promoters. Analysis of the resulting cell lines revealed that oCGIs act as tethering elements that promote the physical and functional communication between poised enhancers and distally located genes, particularly those with large CGI clusters in their promoters. Therefore, by acting as genetic determinants of gene–enhancer compatibility, CGIs can contribute to gene expression control under both physiological and potentially pathological conditions.
Genetic manipulation of poised enhancers (PEs) shows that orphan CpG islands promote physical and functional communication between PEs and distally located developmental genes. |
| doi_str_mv | 10.1038/s41588-021-00888-x |
| format | Article |
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Genetic manipulation of poised enhancers (PEs) shows that orphan CpG islands promote physical and functional communication between PEs and distally located developmental genes.</description><identifier>ISSN: 1061-4036</identifier><identifier>EISSN: 1546-1718</identifier><identifier>DOI: 10.1038/s41588-021-00888-x</identifier><identifier>PMID: 34183853</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>631/136/532 ; 631/208/176 ; 631/208/199 ; 631/208/200 ; Agriculture ; Animal Genetics and Genomics ; Animals ; Binding sites ; Biomedical and Life Sciences ; Biomedicine ; Cancer Research ; Cell lines ; Chromatin ; Chromatin - genetics ; Chromatin - metabolism ; CpG Islands ; DNA ; DNA Methylation ; Embryo cells ; Embryonic Stem Cells - metabolism ; Enhancer Elements, Genetic ; Enhancers ; Epigenesis, Genetic ; Gene expression ; Gene Expression Regulation ; Gene Function ; Gene Knock-In Techniques ; Genes ; Genetic engineering ; Genetic regulation ; Genetic research ; Genomes ; Human Genetics ; Islands ; Mice ; Promoter Regions, Genetic ; Promoters ; Promoters (Genetics) ; Stem cell transplantation ; Stem cells ; Structure ; Tethering ; Transcription initiation ; Vertebrates</subject><ispartof>Nature genetics, 2021-07, Vol.53 (7), p.1036-1049</ispartof><rights>The Author(s), under exclusive licence to Springer Nature America, Inc. 2021</rights><rights>2021. The Author(s), under exclusive licence to Springer Nature America, Inc.</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c609t-2303317a376f3727eae99e33eef8c93f36c99825e038479c258a20e28379518d3</citedby><cites>FETCH-LOGICAL-c609t-2303317a376f3727eae99e33eef8c93f36c99825e038479c258a20e28379518d3</cites><orcidid>0000-0001-7137-1341 ; 0000-0002-7249-5343 ; 0000-0002-9405-2244 ; 0000-0003-1904-1606 ; 0000-0003-2823-7715 ; 0000-0002-0421-8301</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41588-021-00888-x$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41588-021-00888-x$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>230,314,780,784,885,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34183853$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pachano, Tomas</creatorcontrib><creatorcontrib>Sánchez-Gaya, Víctor</creatorcontrib><creatorcontrib>Ealo, Thais</creatorcontrib><creatorcontrib>Mariner-Faulí, Maria</creatorcontrib><creatorcontrib>Bleckwehl, Tore</creatorcontrib><creatorcontrib>Asenjo, Helena G.</creatorcontrib><creatorcontrib>Respuela, Patricia</creatorcontrib><creatorcontrib>Cruz-Molina, Sara</creatorcontrib><creatorcontrib>Muñoz-San Martín, María</creatorcontrib><creatorcontrib>Haro, Endika</creatorcontrib><creatorcontrib>van IJcken, Wilfred F. J.</creatorcontrib><creatorcontrib>Landeira, David</creatorcontrib><creatorcontrib>Rada-Iglesias, Alvaro</creatorcontrib><title>Orphan CpG islands amplify poised enhancer regulatory activity and determine target gene responsiveness</title><title>Nature genetics</title><addtitle>Nat Genet</addtitle><addtitle>Nat Genet</addtitle><description>CpG islands (CGIs) represent a widespread feature of vertebrate genomes, being associated with ~70% of all gene promoters. CGIs control transcription initiation by conferring nearby promoters with unique chromatin properties. In addition, there are thousands of distal or orphan CGIs (oCGIs) whose functional relevance is barely known. Here we show that oCGIs are an essential component of poised enhancers that augment their long-range regulatory activity and control the responsiveness of their target genes. Using a knock-in strategy in mouse embryonic stem cells, we introduced poised enhancers with or without oCGIs within topologically associating domains harboring genes with different types of promoters. Analysis of the resulting cell lines revealed that oCGIs act as tethering elements that promote the physical and functional communication between poised enhancers and distally located genes, particularly those with large CGI clusters in their promoters. Therefore, by acting as genetic determinants of gene–enhancer compatibility, CGIs can contribute to gene expression control under both physiological and potentially pathological conditions.
Genetic manipulation of poised enhancers (PEs) shows that orphan CpG islands promote physical and functional communication between PEs and distally located developmental genes.</description><subject>631/136/532</subject><subject>631/208/176</subject><subject>631/208/199</subject><subject>631/208/200</subject><subject>Agriculture</subject><subject>Animal Genetics and Genomics</subject><subject>Animals</subject><subject>Binding sites</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cancer Research</subject><subject>Cell lines</subject><subject>Chromatin</subject><subject>Chromatin - genetics</subject><subject>Chromatin - metabolism</subject><subject>CpG Islands</subject><subject>DNA</subject><subject>DNA Methylation</subject><subject>Embryo cells</subject><subject>Embryonic Stem Cells - metabolism</subject><subject>Enhancer Elements, Genetic</subject><subject>Enhancers</subject><subject>Epigenesis, Genetic</subject><subject>Gene expression</subject><subject>Gene Expression Regulation</subject><subject>Gene Function</subject><subject>Gene Knock-In Techniques</subject><subject>Genes</subject><subject>Genetic engineering</subject><subject>Genetic regulation</subject><subject>Genetic research</subject><subject>Genomes</subject><subject>Human Genetics</subject><subject>Islands</subject><subject>Mice</subject><subject>Promoter Regions, Genetic</subject><subject>Promoters</subject><subject>Promoters (Genetics)</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Structure</subject><subject>Tethering</subject><subject>Transcription initiation</subject><subject>Vertebrates</subject><issn>1061-4036</issn><issn>1546-1718</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNkl1rFDEUhgdRbK3-AS9kwBu9mJqPSSa5EcqitVBY8Os2xMyZacpMZkwyy-6_99StrSsikoucJM95w3l5i-I5JaeUcPUm1VQoVRFGK0IUVtsHxTEVtaxoQ9VDrImkVU24PCqepHRNCK1roh4XR7ymiivBj4t-HecrG8rVfF76NNjQptKO8-C7XTlPPkFbQkDAQSwj9Mtg8xR3pXXZb3zGIrRlCxni6AOU2cYectkD1hHSPIXkN3hI6WnxqLNDgme3-0nx5f27z6sP1eX6_GJ1dlk5SXSuGCec08byRna8YQ1Y0Bo4B-iU07zj0mmtmACcv260Y0JZRoAp3mhBVctPird73Xn5NkLrIORoBzNHP9q4M5P15vAl-CvTTxvTSEqpYijw6lYgTt8XSNmMPjkY0BqYlmQY-iu01HWD6Ms_0OtpiQHHQ0oQIYlg8p7q7QDGh27Cf92NqDmTstG61kIjdfoXClcLo3dTgM7j_UHD64MGZDJsc2-XlMzFp4__z66_HrJsz7o4pRShu_OOEnMTO7OPncHYmZ-xM1tsevG763ctv3KGAN8DCZ9CD_Heqn_I_gCwPuHZ</recordid><startdate>20210701</startdate><enddate>20210701</enddate><creator>Pachano, Tomas</creator><creator>Sánchez-Gaya, Víctor</creator><creator>Ealo, Thais</creator><creator>Mariner-Faulí, Maria</creator><creator>Bleckwehl, Tore</creator><creator>Asenjo, Helena G.</creator><creator>Respuela, Patricia</creator><creator>Cruz-Molina, Sara</creator><creator>Muñoz-San Martín, María</creator><creator>Haro, Endika</creator><creator>van IJcken, Wilfred F. 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Here we show that oCGIs are an essential component of poised enhancers that augment their long-range regulatory activity and control the responsiveness of their target genes. Using a knock-in strategy in mouse embryonic stem cells, we introduced poised enhancers with or without oCGIs within topologically associating domains harboring genes with different types of promoters. Analysis of the resulting cell lines revealed that oCGIs act as tethering elements that promote the physical and functional communication between poised enhancers and distally located genes, particularly those with large CGI clusters in their promoters. Therefore, by acting as genetic determinants of gene–enhancer compatibility, CGIs can contribute to gene expression control under both physiological and potentially pathological conditions.
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| ispartof | Nature genetics, 2021-07, Vol.53 (7), p.1036-1049 |
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| language | eng |
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| source | MEDLINE; Springer Nature - Complete Springer Journals; Springer Nature - Connect here FIRST to enable access |
| subjects | 631/136/532 631/208/176 631/208/199 631/208/200 Agriculture Animal Genetics and Genomics Animals Binding sites Biomedical and Life Sciences Biomedicine Cancer Research Cell lines Chromatin Chromatin - genetics Chromatin - metabolism CpG Islands DNA DNA Methylation Embryo cells Embryonic Stem Cells - metabolism Enhancer Elements, Genetic Enhancers Epigenesis, Genetic Gene expression Gene Expression Regulation Gene Function Gene Knock-In Techniques Genes Genetic engineering Genetic regulation Genetic research Genomes Human Genetics Islands Mice Promoter Regions, Genetic Promoters Promoters (Genetics) Stem cell transplantation Stem cells Structure Tethering Transcription initiation Vertebrates |
| title | Orphan CpG islands amplify poised enhancer regulatory activity and determine target gene responsiveness |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-01T07%3A26%3A14IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Orphan%20CpG%20islands%20amplify%20poised%20enhancer%20regulatory%20activity%20and%20determine%20target%20gene%20responsiveness&rft.jtitle=Nature%20genetics&rft.au=Pachano,%20Tomas&rft.date=2021-07-01&rft.volume=53&rft.issue=7&rft.spage=1036&rft.epage=1049&rft.pages=1036-1049&rft.issn=1061-4036&rft.eissn=1546-1718&rft_id=info:doi/10.1038/s41588-021-00888-x&rft_dat=%3Cgale_pubme%3EA667994959%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2550560526&rft_id=info:pmid/34183853&rft_galeid=A667994959&rfr_iscdi=true |