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Interaction of the NRF2 and p63 transcription factors promotes keratinocyte proliferation in the epidermis
Abstract Epigenetic regulation of cell and tissue function requires the coordinated action of transcription factors. However, their combinatorial activities during regeneration remain largely unexplored. Here, we discover an unexpected interaction between the cytoprotective transcription factor NRF2...
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Published in: | Nucleic acids research 2021-04, Vol.49 (7), p.3748-3763 |
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container_title | Nucleic acids research |
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creator | Kurinna, Svitlana Seltmann, Kristin Bachmann, Andreas L Schwendimann, Andreas Thiagarajan, Lalitha Hennig, Paulina Beer, Hans-Dietmar Mollo, Maria Rosaria Missero, Caterina Werner, Sabine |
description | Abstract
Epigenetic regulation of cell and tissue function requires the coordinated action of transcription factors. However, their combinatorial activities during regeneration remain largely unexplored. Here, we discover an unexpected interaction between the cytoprotective transcription factor NRF2 and p63- a key player in epithelial morphogenesis. Chromatin immunoprecipitation combined with sequencing and reporter assays identifies enhancers and promoters that are simultaneously activated by NRF2 and p63 in human keratinocytes. Modeling of p63 and NRF2 binding to nucleosomal DNA suggests their chromatin-assisted interaction. Pharmacological and genetic activation of NRF2 increases NRF2–p63 binding to enhancers and promotes keratinocyte proliferation, which involves the common NRF2–p63 target cyclin-dependent kinase 12. These results unravel a collaborative function of NRF2 and p63 in the control of epidermal renewal and suggest their combined activation as a strategy to promote repair of human skin and other stratified epithelia. |
doi_str_mv | 10.1093/nar/gkab167 |
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Epigenetic regulation of cell and tissue function requires the coordinated action of transcription factors. However, their combinatorial activities during regeneration remain largely unexplored. Here, we discover an unexpected interaction between the cytoprotective transcription factor NRF2 and p63- a key player in epithelial morphogenesis. Chromatin immunoprecipitation combined with sequencing and reporter assays identifies enhancers and promoters that are simultaneously activated by NRF2 and p63 in human keratinocytes. Modeling of p63 and NRF2 binding to nucleosomal DNA suggests their chromatin-assisted interaction. Pharmacological and genetic activation of NRF2 increases NRF2–p63 binding to enhancers and promotes keratinocyte proliferation, which involves the common NRF2–p63 target cyclin-dependent kinase 12. These results unravel a collaborative function of NRF2 and p63 in the control of epidermal renewal and suggest their combined activation as a strategy to promote repair of human skin and other stratified epithelia.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkab167</identifier><identifier>PMID: 33764436</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Animals ; Cell Proliferation ; Cells, Cultured ; Cyclin-Dependent Kinases - metabolism ; Data Resources and Analyses ; Humans ; Keratinocytes - cytology ; Keratinocytes - metabolism ; Mice ; NF-E2-Related Factor 2 - physiology ; Skin - cytology ; Skin - metabolism ; Transcription Factors - physiology ; Tumor Suppressor Proteins - physiology</subject><ispartof>Nucleic acids research, 2021-04, Vol.49 (7), p.3748-3763</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-c478t-317d28445681946c9e95b33ece17024cd15028ca0e9585eb110d390262094c0d3</citedby><cites>FETCH-LOGICAL-c478t-317d28445681946c9e95b33ece17024cd15028ca0e9585eb110d390262094c0d3</cites><orcidid>0000-0002-2157-667X</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/PMC8053124/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053124/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,1603,27922,27923,53789,53791</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33764436$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Kurinna, Svitlana</creatorcontrib><creatorcontrib>Seltmann, Kristin</creatorcontrib><creatorcontrib>Bachmann, Andreas L</creatorcontrib><creatorcontrib>Schwendimann, Andreas</creatorcontrib><creatorcontrib>Thiagarajan, Lalitha</creatorcontrib><creatorcontrib>Hennig, Paulina</creatorcontrib><creatorcontrib>Beer, Hans-Dietmar</creatorcontrib><creatorcontrib>Mollo, Maria Rosaria</creatorcontrib><creatorcontrib>Missero, Caterina</creatorcontrib><creatorcontrib>Werner, Sabine</creatorcontrib><title>Interaction of the NRF2 and p63 transcription factors promotes keratinocyte proliferation in the epidermis</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>Abstract
Epigenetic regulation of cell and tissue function requires the coordinated action of transcription factors. However, their combinatorial activities during regeneration remain largely unexplored. Here, we discover an unexpected interaction between the cytoprotective transcription factor NRF2 and p63- a key player in epithelial morphogenesis. Chromatin immunoprecipitation combined with sequencing and reporter assays identifies enhancers and promoters that are simultaneously activated by NRF2 and p63 in human keratinocytes. Modeling of p63 and NRF2 binding to nucleosomal DNA suggests their chromatin-assisted interaction. Pharmacological and genetic activation of NRF2 increases NRF2–p63 binding to enhancers and promotes keratinocyte proliferation, which involves the common NRF2–p63 target cyclin-dependent kinase 12. These results unravel a collaborative function of NRF2 and p63 in the control of epidermal renewal and suggest their combined activation as a strategy to promote repair of human skin and other stratified epithelia.</description><subject>Animals</subject><subject>Cell Proliferation</subject><subject>Cells, Cultured</subject><subject>Cyclin-Dependent Kinases - metabolism</subject><subject>Data Resources and Analyses</subject><subject>Humans</subject><subject>Keratinocytes - cytology</subject><subject>Keratinocytes - metabolism</subject><subject>Mice</subject><subject>NF-E2-Related Factor 2 - physiology</subject><subject>Skin - cytology</subject><subject>Skin - metabolism</subject><subject>Transcription Factors - physiology</subject><subject>Tumor Suppressor Proteins - physiology</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>TOX</sourceid><recordid>eNp9kUtLxDAURoMoOo6u3EtXIkg1r6btRpDBx8CgILoOmfR2jHaSmmQE_72Zh6IbVwlfTk5u-BA6Ivic4JpdWOUvZm9qSkS5hQaECZrzWtBtNMAMFznBvNpD-yG8Ykw4Kfgu2mOsFJwzMUCvYxvBKx2Ns5lrs_gC2f3jDc2UbbJesCx6ZYP2pl8RbSKdD1nv3dxFCNlbuhyNdfozwjLtTLtKEmvsyga9acDPTThAO63qAhxu1iF6vrl-Gt3lk4fb8ehqkmteVjFnpGxoxXkhKlJzoWuoiyljoIGUmHLdkALTSiuc8qqAKSG4YTWmguKa67Qfosu1t19M59BosOkPney9mSv_KZ0y8u-JNS9y5j5khQtGKE-C043Au_cFhCjT9Bq6TllwiyBpkUDBa7ZEz9ao9i4ED-3PMwTLZTsytSM37ST6-PdkP-x3HQk4WQNu0f9r-gKVqJp_</recordid><startdate>20210419</startdate><enddate>20210419</enddate><creator>Kurinna, Svitlana</creator><creator>Seltmann, Kristin</creator><creator>Bachmann, Andreas L</creator><creator>Schwendimann, Andreas</creator><creator>Thiagarajan, Lalitha</creator><creator>Hennig, Paulina</creator><creator>Beer, Hans-Dietmar</creator><creator>Mollo, Maria Rosaria</creator><creator>Missero, Caterina</creator><creator>Werner, Sabine</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/0000-0002-2157-667X</orcidid></search><sort><creationdate>20210419</creationdate><title>Interaction of the NRF2 and p63 transcription factors promotes keratinocyte proliferation in the epidermis</title><author>Kurinna, Svitlana ; Seltmann, Kristin ; Bachmann, Andreas L ; Schwendimann, Andreas ; Thiagarajan, Lalitha ; Hennig, Paulina ; Beer, Hans-Dietmar ; Mollo, Maria Rosaria ; Missero, Caterina ; Werner, Sabine</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c478t-317d28445681946c9e95b33ece17024cd15028ca0e9585eb110d390262094c0d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Animals</topic><topic>Cell Proliferation</topic><topic>Cells, Cultured</topic><topic>Cyclin-Dependent Kinases - metabolism</topic><topic>Data Resources and Analyses</topic><topic>Humans</topic><topic>Keratinocytes - cytology</topic><topic>Keratinocytes - metabolism</topic><topic>Mice</topic><topic>NF-E2-Related Factor 2 - physiology</topic><topic>Skin - cytology</topic><topic>Skin - metabolism</topic><topic>Transcription Factors - physiology</topic><topic>Tumor Suppressor Proteins - physiology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Kurinna, Svitlana</creatorcontrib><creatorcontrib>Seltmann, Kristin</creatorcontrib><creatorcontrib>Bachmann, Andreas L</creatorcontrib><creatorcontrib>Schwendimann, Andreas</creatorcontrib><creatorcontrib>Thiagarajan, Lalitha</creatorcontrib><creatorcontrib>Hennig, Paulina</creatorcontrib><creatorcontrib>Beer, Hans-Dietmar</creatorcontrib><creatorcontrib>Mollo, Maria Rosaria</creatorcontrib><creatorcontrib>Missero, Caterina</creatorcontrib><creatorcontrib>Werner, Sabine</creatorcontrib><collection>Open Access: Oxford University Press Open Journals</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>Kurinna, Svitlana</au><au>Seltmann, Kristin</au><au>Bachmann, Andreas L</au><au>Schwendimann, Andreas</au><au>Thiagarajan, Lalitha</au><au>Hennig, Paulina</au><au>Beer, Hans-Dietmar</au><au>Mollo, Maria Rosaria</au><au>Missero, Caterina</au><au>Werner, Sabine</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Interaction of the NRF2 and p63 transcription factors promotes keratinocyte proliferation in the epidermis</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2021-04-19</date><risdate>2021</risdate><volume>49</volume><issue>7</issue><spage>3748</spage><epage>3763</epage><pages>3748-3763</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><abstract>Abstract
Epigenetic regulation of cell and tissue function requires the coordinated action of transcription factors. However, their combinatorial activities during regeneration remain largely unexplored. Here, we discover an unexpected interaction between the cytoprotective transcription factor NRF2 and p63- a key player in epithelial morphogenesis. Chromatin immunoprecipitation combined with sequencing and reporter assays identifies enhancers and promoters that are simultaneously activated by NRF2 and p63 in human keratinocytes. Modeling of p63 and NRF2 binding to nucleosomal DNA suggests their chromatin-assisted interaction. Pharmacological and genetic activation of NRF2 increases NRF2–p63 binding to enhancers and promotes keratinocyte proliferation, which involves the common NRF2–p63 target cyclin-dependent kinase 12. These results unravel a collaborative function of NRF2 and p63 in the control of epidermal renewal and suggest their combined activation as a strategy to promote repair of human skin and other stratified epithelia.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>33764436</pmid><doi>10.1093/nar/gkab167</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-2157-667X</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Animals Cell Proliferation Cells, Cultured Cyclin-Dependent Kinases - metabolism Data Resources and Analyses Humans Keratinocytes - cytology Keratinocytes - metabolism Mice NF-E2-Related Factor 2 - physiology Skin - cytology Skin - metabolism Transcription Factors - physiology Tumor Suppressor Proteins - physiology |
title | Interaction of the NRF2 and p63 transcription factors promotes keratinocyte proliferation in the epidermis |
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