Epigenetic remodelling of enhancers in response to estrogen deprivation and re-stimulation
Abstract Estrogen hormones are implicated in a majority of breast cancers and estrogen receptor alpha (ER), the main nuclear factor mediating estrogen signaling, orchestrates a complex molecular circuitry that is not yet fully elucidated. Here, we investigated genome-wide DNA methylation, histone ac...
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Veröffentlicht in: | Nucleic acids research 2021-09, Vol.49 (17), p.9738-9754 |
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creator | Sklias, Athena Halaburkova, Andrea Vanzan, Ludovica Jimenez, Nora Fernandez Cuenin, Cyrille Bouaoun, Liacine Cahais, Vincent Ythier, Victor Sallé, Aurélie Renard, Claire Durand, Geoffroy Le Calvez-Kelm, Florence Khoueiry, Rita Murr, Rabih Herceg, Zdenko |
description | Abstract
Estrogen hormones are implicated in a majority of breast cancers and estrogen receptor alpha (ER), the main nuclear factor mediating estrogen signaling, orchestrates a complex molecular circuitry that is not yet fully elucidated. Here, we investigated genome-wide DNA methylation, histone acetylation and transcription after estradiol (E2) deprivation and re-stimulation to better characterize the ability of ER to coordinate gene regulation. We found that E2 deprivation mostly resulted in DNA hypermethylation and histone deacetylation in enhancers. Transcriptome analysis revealed that E2 deprivation leads to a global down-regulation in gene expression, and more specifically of TET2 demethylase that may be involved in the DNA hypermethylation following short-term E2 deprivation. Further enrichment analysis of transcription factor (TF) binding and motif occurrence highlights the importance of ER connection mainly with two partner TF families, AP-1 and FOX. These interactions take place in the proximity of E2 deprivation-mediated differentially methylated and histone acetylated enhancers. Finally, while most deprivation-dependent epigenetic changes were reversed following E2 re-stimulation, DNA hypermethylation and H3K27 deacetylation at certain enhancers were partially retained. Overall, these results show that inactivation of ER mediates rapid and mostly reversible epigenetic changes at enhancers, and bring new insight into early events, which may ultimately lead to endocrine resistance. |
doi_str_mv | 10.1093/nar/gkab697 |
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Estrogen hormones are implicated in a majority of breast cancers and estrogen receptor alpha (ER), the main nuclear factor mediating estrogen signaling, orchestrates a complex molecular circuitry that is not yet fully elucidated. Here, we investigated genome-wide DNA methylation, histone acetylation and transcription after estradiol (E2) deprivation and re-stimulation to better characterize the ability of ER to coordinate gene regulation. We found that E2 deprivation mostly resulted in DNA hypermethylation and histone deacetylation in enhancers. Transcriptome analysis revealed that E2 deprivation leads to a global down-regulation in gene expression, and more specifically of TET2 demethylase that may be involved in the DNA hypermethylation following short-term E2 deprivation. Further enrichment analysis of transcription factor (TF) binding and motif occurrence highlights the importance of ER connection mainly with two partner TF families, AP-1 and FOX. These interactions take place in the proximity of E2 deprivation-mediated differentially methylated and histone acetylated enhancers. Finally, while most deprivation-dependent epigenetic changes were reversed following E2 re-stimulation, DNA hypermethylation and H3K27 deacetylation at certain enhancers were partially retained. Overall, these results show that inactivation of ER mediates rapid and mostly reversible epigenetic changes at enhancers, and bring new insight into early events, which may ultimately lead to endocrine resistance.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkab697</identifier><identifier>PMID: 34403459</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>CpG Islands ; Dioxygenases - metabolism ; DNA Methylation ; DNA-Binding Proteins - metabolism ; Enhancer Elements, Genetic ; Epigenesis, Genetic ; Estradiol - physiology ; Gene regulation, Chromatin and Epigenetics ; Histone Code ; Humans ; MCF-7 Cells ; Receptors, Estrogen - metabolism ; Transcription, Genetic</subject><ispartof>Nucleic acids research, 2021-09, Vol.49 (17), p.9738-9754</ispartof><rights>The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. 2021</rights><rights>The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c454t-8584a7af0b4be6d21555d5c421a5f8619d83210988dfd535610a7ee5481f12253</citedby><cites>FETCH-LOGICAL-c454t-8584a7af0b4be6d21555d5c421a5f8619d83210988dfd535610a7ee5481f12253</cites><orcidid>0000-0003-4109-3154</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/PMC8464064/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464064/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,1604,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34403459$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sklias, Athena</creatorcontrib><creatorcontrib>Halaburkova, Andrea</creatorcontrib><creatorcontrib>Vanzan, Ludovica</creatorcontrib><creatorcontrib>Jimenez, Nora Fernandez</creatorcontrib><creatorcontrib>Cuenin, Cyrille</creatorcontrib><creatorcontrib>Bouaoun, Liacine</creatorcontrib><creatorcontrib>Cahais, Vincent</creatorcontrib><creatorcontrib>Ythier, Victor</creatorcontrib><creatorcontrib>Sallé, Aurélie</creatorcontrib><creatorcontrib>Renard, Claire</creatorcontrib><creatorcontrib>Durand, Geoffroy</creatorcontrib><creatorcontrib>Le Calvez-Kelm, Florence</creatorcontrib><creatorcontrib>Khoueiry, Rita</creatorcontrib><creatorcontrib>Murr, Rabih</creatorcontrib><creatorcontrib>Herceg, Zdenko</creatorcontrib><title>Epigenetic remodelling of enhancers in response to estrogen deprivation and re-stimulation</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>Abstract
Estrogen hormones are implicated in a majority of breast cancers and estrogen receptor alpha (ER), the main nuclear factor mediating estrogen signaling, orchestrates a complex molecular circuitry that is not yet fully elucidated. Here, we investigated genome-wide DNA methylation, histone acetylation and transcription after estradiol (E2) deprivation and re-stimulation to better characterize the ability of ER to coordinate gene regulation. We found that E2 deprivation mostly resulted in DNA hypermethylation and histone deacetylation in enhancers. Transcriptome analysis revealed that E2 deprivation leads to a global down-regulation in gene expression, and more specifically of TET2 demethylase that may be involved in the DNA hypermethylation following short-term E2 deprivation. Further enrichment analysis of transcription factor (TF) binding and motif occurrence highlights the importance of ER connection mainly with two partner TF families, AP-1 and FOX. These interactions take place in the proximity of E2 deprivation-mediated differentially methylated and histone acetylated enhancers. Finally, while most deprivation-dependent epigenetic changes were reversed following E2 re-stimulation, DNA hypermethylation and H3K27 deacetylation at certain enhancers were partially retained. Overall, these results show that inactivation of ER mediates rapid and mostly reversible epigenetic changes at enhancers, and bring new insight into early events, which may ultimately lead to endocrine resistance.</description><subject>CpG Islands</subject><subject>Dioxygenases - metabolism</subject><subject>DNA Methylation</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Enhancer Elements, Genetic</subject><subject>Epigenesis, Genetic</subject><subject>Estradiol - physiology</subject><subject>Gene regulation, Chromatin and Epigenetics</subject><subject>Histone Code</subject><subject>Humans</subject><subject>MCF-7 Cells</subject><subject>Receptors, Estrogen - metabolism</subject><subject>Transcription, Genetic</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><sourceid>EIF</sourceid><recordid>eNp9kc1LxDAQxYMo7vpx8i49iSDVJE2y6UWQZf2ABS968RKyzXSNtklN2gX_e6O7il48DWR-efNmHkJHBJ8TXBYXToeL5ateiHKyhcakEDRnpaDbaIwLzHOCmRyhvRhfMCaMcLaLRgVjuGC8HKOnWWeX4KC3VRag9Qaaxrpl5usM3LN2FYSYWZd6sfMuQtb7DGIffPqUGeiCXeneepdpZxKUx962Q_P1dIB2at1EONzUffR4PXuY3ubz-5u76dU8rxhnfS65ZHqia7xgCxCGEs654RWjRPNaClIaWdC0qJSmNrzggmA9AeBMkppQyot9dLnW7YZFC6YC1wfdqGSt1eFdeW3V346zz2rpV0oywbBgSeB0IxD825C2U62NVTqEduCHqCgXlCdfZZnQszVaBR9jgPpnDMHqMw2V0lCbNBJ9_NvZD_t9_gScrAE_dP8qfQBWB5W1</recordid><startdate>20210927</startdate><enddate>20210927</enddate><creator>Sklias, Athena</creator><creator>Halaburkova, Andrea</creator><creator>Vanzan, Ludovica</creator><creator>Jimenez, Nora Fernandez</creator><creator>Cuenin, Cyrille</creator><creator>Bouaoun, Liacine</creator><creator>Cahais, Vincent</creator><creator>Ythier, Victor</creator><creator>Sallé, Aurélie</creator><creator>Renard, Claire</creator><creator>Durand, Geoffroy</creator><creator>Le Calvez-Kelm, Florence</creator><creator>Khoueiry, Rita</creator><creator>Murr, Rabih</creator><creator>Herceg, Zdenko</creator><general>Oxford University Press</general><scope>TOX</scope><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/0000-0003-4109-3154</orcidid></search><sort><creationdate>20210927</creationdate><title>Epigenetic remodelling of enhancers in response to estrogen deprivation and re-stimulation</title><author>Sklias, Athena ; Halaburkova, Andrea ; Vanzan, Ludovica ; Jimenez, Nora Fernandez ; Cuenin, Cyrille ; Bouaoun, Liacine ; Cahais, Vincent ; Ythier, Victor ; Sallé, Aurélie ; Renard, Claire ; Durand, Geoffroy ; Le Calvez-Kelm, Florence ; Khoueiry, Rita ; Murr, Rabih ; Herceg, Zdenko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c454t-8584a7af0b4be6d21555d5c421a5f8619d83210988dfd535610a7ee5481f12253</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>CpG Islands</topic><topic>Dioxygenases - metabolism</topic><topic>DNA Methylation</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Enhancer Elements, Genetic</topic><topic>Epigenesis, Genetic</topic><topic>Estradiol - physiology</topic><topic>Gene regulation, Chromatin and Epigenetics</topic><topic>Histone Code</topic><topic>Humans</topic><topic>MCF-7 Cells</topic><topic>Receptors, Estrogen - metabolism</topic><topic>Transcription, Genetic</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sklias, Athena</creatorcontrib><creatorcontrib>Halaburkova, Andrea</creatorcontrib><creatorcontrib>Vanzan, Ludovica</creatorcontrib><creatorcontrib>Jimenez, Nora Fernandez</creatorcontrib><creatorcontrib>Cuenin, Cyrille</creatorcontrib><creatorcontrib>Bouaoun, Liacine</creatorcontrib><creatorcontrib>Cahais, Vincent</creatorcontrib><creatorcontrib>Ythier, Victor</creatorcontrib><creatorcontrib>Sallé, Aurélie</creatorcontrib><creatorcontrib>Renard, Claire</creatorcontrib><creatorcontrib>Durand, Geoffroy</creatorcontrib><creatorcontrib>Le Calvez-Kelm, Florence</creatorcontrib><creatorcontrib>Khoueiry, Rita</creatorcontrib><creatorcontrib>Murr, Rabih</creatorcontrib><creatorcontrib>Herceg, Zdenko</creatorcontrib><collection>Oxford Journals Open Access Collection</collection><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>Nucleic acids research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sklias, Athena</au><au>Halaburkova, Andrea</au><au>Vanzan, Ludovica</au><au>Jimenez, Nora Fernandez</au><au>Cuenin, Cyrille</au><au>Bouaoun, Liacine</au><au>Cahais, Vincent</au><au>Ythier, Victor</au><au>Sallé, Aurélie</au><au>Renard, Claire</au><au>Durand, Geoffroy</au><au>Le Calvez-Kelm, Florence</au><au>Khoueiry, Rita</au><au>Murr, Rabih</au><au>Herceg, Zdenko</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Epigenetic remodelling of enhancers in response to estrogen deprivation and re-stimulation</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2021-09-27</date><risdate>2021</risdate><volume>49</volume><issue>17</issue><spage>9738</spage><epage>9754</epage><pages>9738-9754</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><abstract>Abstract
Estrogen hormones are implicated in a majority of breast cancers and estrogen receptor alpha (ER), the main nuclear factor mediating estrogen signaling, orchestrates a complex molecular circuitry that is not yet fully elucidated. Here, we investigated genome-wide DNA methylation, histone acetylation and transcription after estradiol (E2) deprivation and re-stimulation to better characterize the ability of ER to coordinate gene regulation. We found that E2 deprivation mostly resulted in DNA hypermethylation and histone deacetylation in enhancers. Transcriptome analysis revealed that E2 deprivation leads to a global down-regulation in gene expression, and more specifically of TET2 demethylase that may be involved in the DNA hypermethylation following short-term E2 deprivation. Further enrichment analysis of transcription factor (TF) binding and motif occurrence highlights the importance of ER connection mainly with two partner TF families, AP-1 and FOX. These interactions take place in the proximity of E2 deprivation-mediated differentially methylated and histone acetylated enhancers. Finally, while most deprivation-dependent epigenetic changes were reversed following E2 re-stimulation, DNA hypermethylation and H3K27 deacetylation at certain enhancers were partially retained. Overall, these results show that inactivation of ER mediates rapid and mostly reversible epigenetic changes at enhancers, and bring new insight into early events, which may ultimately lead to endocrine resistance.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>34403459</pmid><doi>10.1093/nar/gkab697</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0003-4109-3154</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | CpG Islands Dioxygenases - metabolism DNA Methylation DNA-Binding Proteins - metabolism Enhancer Elements, Genetic Epigenesis, Genetic Estradiol - physiology Gene regulation, Chromatin and Epigenetics Histone Code Humans MCF-7 Cells Receptors, Estrogen - metabolism Transcription, Genetic |
title | Epigenetic remodelling of enhancers in response to estrogen deprivation and re-stimulation |
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