Genome-wide analysis of p63 binding sites identifies AP-2 factors as co-regulators of epidermal differentiation
The p63 transcription factor (TP63) is critical in development, growth and differentiation of stratifying epithelia. This is highlighted by the severity of congenital abnormalities caused by TP63 mutations in humans, the dramatic phenotypes in knockout mice and de-regulation of TP63 expression in ne...
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Veröffentlicht in: | Nucleic acids research 2012-08, Vol.40 (15), p.7190-7206 |
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creator | McDade, Simon S Henry, Alexandra E Pivato, Geraldine P Kozarewa, Iwanka Mitsopoulos, Constantinos Fenwick, Kerry Assiotis, Ioannis Hakas, Jarle Zvelebil, Marketa Orr, Nicholas Lord, Christopher J Patel, Daksha Ashworth, Alan McCance, Dennis J |
description | The p63 transcription factor (TP63) is critical in development, growth and differentiation of stratifying epithelia. This is highlighted by the severity of congenital abnormalities caused by TP63 mutations in humans, the dramatic phenotypes in knockout mice and de-regulation of TP63 expression in neoplasia altering the tumour suppressive roles of the TP53 family. In order to define the normal role played by TP63 and provide the basis for better understanding how this network is perturbed in disease, we used chromatin immunoprecipitation combined with massively parallel sequencing (ChIP-seq) to identify >7500 high-confidence TP63-binding regions across the entire genome, in primary human neonatal foreskin keratinocytes (HFKs). Using integrative strategies, we demonstrate that only a subset of these sites are bound by TP53 in response to DNA damage. We identify a role for TP63 in transcriptional regulation of multiple genes genetically linked to cleft palate and identify AP-2alpha (TFAP2A) as a co-regulator of a subset of these genes. We further demonstrate that AP-2gamma (TFAP2C) can bind a subset of these regions and that acute depletion of either TFAP2A or TFAP2C alone is sufficient to reduce terminal differentiation of organotypic epidermal skin equivalents, indicating overlapping physiological functions with TP63. |
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This is highlighted by the severity of congenital abnormalities caused by TP63 mutations in humans, the dramatic phenotypes in knockout mice and de-regulation of TP63 expression in neoplasia altering the tumour suppressive roles of the TP53 family. In order to define the normal role played by TP63 and provide the basis for better understanding how this network is perturbed in disease, we used chromatin immunoprecipitation combined with massively parallel sequencing (ChIP-seq) to identify >7500 high-confidence TP63-binding regions across the entire genome, in primary human neonatal foreskin keratinocytes (HFKs). Using integrative strategies, we demonstrate that only a subset of these sites are bound by TP53 in response to DNA damage. We identify a role for TP63 in transcriptional regulation of multiple genes genetically linked to cleft palate and identify AP-2alpha (TFAP2A) as a co-regulator of a subset of these genes. We further demonstrate that AP-2gamma (TFAP2C) can bind a subset of these regions and that acute depletion of either TFAP2A or TFAP2C alone is sufficient to reduce terminal differentiation of organotypic epidermal skin equivalents, indicating overlapping physiological functions with TP63.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gks389</identifier><identifier>PMID: 22573176</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>AP-2 protein ; Binding Sites ; Cell Differentiation ; Cells, Cultured ; Chromatin ; Cleft lip/palate ; Cleft Palate - genetics ; Differentiation ; DNA damage ; Epidermal Cells ; Gene Expression Regulation ; Gene regulation ; Gene Regulation, Chromatin and Epigenetics ; Genome, Human ; Genomes ; Humans ; Immunoprecipitation ; Keratinocytes ; Keratinocytes - cytology ; Keratinocytes - metabolism ; Molecular Sequence Annotation ; Mutation ; Neonates ; Neoplasia ; p53 protein ; Regulatory Elements, Transcriptional ; Skin ; Transcription ; Transcription Factor AP-2 - antagonists & inhibitors ; Transcription Factor AP-2 - metabolism ; Transcription factors ; Transcription Factors - metabolism ; Tumor Suppressor Protein p53 - metabolism ; Tumor Suppressor Proteins - metabolism</subject><ispartof>Nucleic acids research, 2012-08, Vol.40 (15), p.7190-7206</ispartof><rights>The Author(s) 2012. Published by Oxford University Press. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3424553/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3424553/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22573176$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>McDade, Simon S</creatorcontrib><creatorcontrib>Henry, Alexandra E</creatorcontrib><creatorcontrib>Pivato, Geraldine P</creatorcontrib><creatorcontrib>Kozarewa, Iwanka</creatorcontrib><creatorcontrib>Mitsopoulos, Constantinos</creatorcontrib><creatorcontrib>Fenwick, Kerry</creatorcontrib><creatorcontrib>Assiotis, Ioannis</creatorcontrib><creatorcontrib>Hakas, Jarle</creatorcontrib><creatorcontrib>Zvelebil, Marketa</creatorcontrib><creatorcontrib>Orr, Nicholas</creatorcontrib><creatorcontrib>Lord, Christopher J</creatorcontrib><creatorcontrib>Patel, Daksha</creatorcontrib><creatorcontrib>Ashworth, Alan</creatorcontrib><creatorcontrib>McCance, Dennis J</creatorcontrib><title>Genome-wide analysis of p63 binding sites identifies AP-2 factors as co-regulators of epidermal differentiation</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><description>The p63 transcription factor (TP63) is critical in development, growth and differentiation of stratifying epithelia. This is highlighted by the severity of congenital abnormalities caused by TP63 mutations in humans, the dramatic phenotypes in knockout mice and de-regulation of TP63 expression in neoplasia altering the tumour suppressive roles of the TP53 family. In order to define the normal role played by TP63 and provide the basis for better understanding how this network is perturbed in disease, we used chromatin immunoprecipitation combined with massively parallel sequencing (ChIP-seq) to identify >7500 high-confidence TP63-binding regions across the entire genome, in primary human neonatal foreskin keratinocytes (HFKs). Using integrative strategies, we demonstrate that only a subset of these sites are bound by TP53 in response to DNA damage. We identify a role for TP63 in transcriptional regulation of multiple genes genetically linked to cleft palate and identify AP-2alpha (TFAP2A) as a co-regulator of a subset of these genes. We further demonstrate that AP-2gamma (TFAP2C) can bind a subset of these regions and that acute depletion of either TFAP2A or TFAP2C alone is sufficient to reduce terminal differentiation of organotypic epidermal skin equivalents, indicating overlapping physiological functions with TP63.</description><subject>AP-2 protein</subject><subject>Binding Sites</subject><subject>Cell Differentiation</subject><subject>Cells, Cultured</subject><subject>Chromatin</subject><subject>Cleft lip/palate</subject><subject>Cleft Palate - genetics</subject><subject>Differentiation</subject><subject>DNA damage</subject><subject>Epidermal Cells</subject><subject>Gene Expression Regulation</subject><subject>Gene regulation</subject><subject>Gene Regulation, Chromatin and Epigenetics</subject><subject>Genome, Human</subject><subject>Genomes</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Keratinocytes</subject><subject>Keratinocytes - cytology</subject><subject>Keratinocytes - metabolism</subject><subject>Molecular Sequence Annotation</subject><subject>Mutation</subject><subject>Neonates</subject><subject>Neoplasia</subject><subject>p53 protein</subject><subject>Regulatory Elements, Transcriptional</subject><subject>Skin</subject><subject>Transcription</subject><subject>Transcription Factor AP-2 - antagonists & inhibitors</subject><subject>Transcription Factor AP-2 - metabolism</subject><subject>Transcription factors</subject><subject>Transcription Factors - metabolism</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumor Suppressor Proteins - metabolism</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkUtLxDAUhYMoOo5u_AGSpZtqHk3abIRh8AUDutB1uZPHGG2TmnQU_731ie5c3cs93zkcuAgdUHJMieInAdLJ6jHzWm2gCeWSFaWSbBNNCCeioKSsd9Buzg-E0JKKchvtMCYqTis5QfHChtjZ4sUbiyFA-5p9xtHhXnK89MH4sMLZDzbjkQiDd35cZzcFww70EFPGkLGORbKrdQsfh9Ft-5FOHbTYeOdsenfC4GPYQ1sO2mz3v-YU3Z2f3c4vi8X1xdV8tih6xtRQUAbOksqAEsRILY2mTJSqtrWgonZGO0JAWaIMGCuEWxrgminDnKq0kppP0elnbr9edtbosUCCtumT7yC9NhF881cJ_r5ZxeeGl6wUgo8BR18BKT6tbR6azmdt2xaCjevcUCIVVZIo9g-UC0pEWb2jh79r_fT5fgh_A8Inj5Y</recordid><startdate>20120801</startdate><enddate>20120801</enddate><creator>McDade, Simon S</creator><creator>Henry, Alexandra E</creator><creator>Pivato, Geraldine P</creator><creator>Kozarewa, Iwanka</creator><creator>Mitsopoulos, Constantinos</creator><creator>Fenwick, Kerry</creator><creator>Assiotis, Ioannis</creator><creator>Hakas, Jarle</creator><creator>Zvelebil, Marketa</creator><creator>Orr, Nicholas</creator><creator>Lord, Christopher J</creator><creator>Patel, Daksha</creator><creator>Ashworth, Alan</creator><creator>McCance, Dennis J</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><scope>7TM</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20120801</creationdate><title>Genome-wide analysis of p63 binding sites identifies AP-2 factors as co-regulators of epidermal differentiation</title><author>McDade, Simon S ; Henry, Alexandra E ; Pivato, Geraldine P ; Kozarewa, Iwanka ; Mitsopoulos, Constantinos ; Fenwick, Kerry ; Assiotis, Ioannis ; Hakas, Jarle ; Zvelebil, Marketa ; Orr, Nicholas ; Lord, Christopher J ; Patel, Daksha ; Ashworth, Alan ; McCance, Dennis J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p229t-12afe07da950d6c6dc125498e85158fdcf00a9e09dade55fbda3c29d2f97c96c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>AP-2 protein</topic><topic>Binding Sites</topic><topic>Cell Differentiation</topic><topic>Cells, Cultured</topic><topic>Chromatin</topic><topic>Cleft lip/palate</topic><topic>Cleft Palate - genetics</topic><topic>Differentiation</topic><topic>DNA damage</topic><topic>Epidermal Cells</topic><topic>Gene Expression Regulation</topic><topic>Gene regulation</topic><topic>Gene Regulation, Chromatin and Epigenetics</topic><topic>Genome, Human</topic><topic>Genomes</topic><topic>Humans</topic><topic>Immunoprecipitation</topic><topic>Keratinocytes</topic><topic>Keratinocytes - cytology</topic><topic>Keratinocytes - metabolism</topic><topic>Molecular Sequence Annotation</topic><topic>Mutation</topic><topic>Neonates</topic><topic>Neoplasia</topic><topic>p53 protein</topic><topic>Regulatory Elements, Transcriptional</topic><topic>Skin</topic><topic>Transcription</topic><topic>Transcription Factor AP-2 - antagonists & inhibitors</topic><topic>Transcription Factor AP-2 - metabolism</topic><topic>Transcription factors</topic><topic>Transcription Factors - metabolism</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><topic>Tumor Suppressor Proteins - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>McDade, Simon S</creatorcontrib><creatorcontrib>Henry, Alexandra E</creatorcontrib><creatorcontrib>Pivato, Geraldine P</creatorcontrib><creatorcontrib>Kozarewa, Iwanka</creatorcontrib><creatorcontrib>Mitsopoulos, Constantinos</creatorcontrib><creatorcontrib>Fenwick, Kerry</creatorcontrib><creatorcontrib>Assiotis, Ioannis</creatorcontrib><creatorcontrib>Hakas, Jarle</creatorcontrib><creatorcontrib>Zvelebil, Marketa</creatorcontrib><creatorcontrib>Orr, Nicholas</creatorcontrib><creatorcontrib>Lord, Christopher J</creatorcontrib><creatorcontrib>Patel, Daksha</creatorcontrib><creatorcontrib>Ashworth, Alan</creatorcontrib><creatorcontrib>McCance, Dennis J</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>Nucleic Acids Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</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>McDade, Simon S</au><au>Henry, Alexandra E</au><au>Pivato, Geraldine P</au><au>Kozarewa, Iwanka</au><au>Mitsopoulos, Constantinos</au><au>Fenwick, Kerry</au><au>Assiotis, Ioannis</au><au>Hakas, Jarle</au><au>Zvelebil, Marketa</au><au>Orr, Nicholas</au><au>Lord, Christopher J</au><au>Patel, Daksha</au><au>Ashworth, Alan</au><au>McCance, Dennis J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Genome-wide analysis of p63 binding sites identifies AP-2 factors as co-regulators of epidermal differentiation</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2012-08-01</date><risdate>2012</risdate><volume>40</volume><issue>15</issue><spage>7190</spage><epage>7206</epage><pages>7190-7206</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><abstract>The p63 transcription factor (TP63) is critical in development, growth and differentiation of stratifying epithelia. This is highlighted by the severity of congenital abnormalities caused by TP63 mutations in humans, the dramatic phenotypes in knockout mice and de-regulation of TP63 expression in neoplasia altering the tumour suppressive roles of the TP53 family. In order to define the normal role played by TP63 and provide the basis for better understanding how this network is perturbed in disease, we used chromatin immunoprecipitation combined with massively parallel sequencing (ChIP-seq) to identify >7500 high-confidence TP63-binding regions across the entire genome, in primary human neonatal foreskin keratinocytes (HFKs). Using integrative strategies, we demonstrate that only a subset of these sites are bound by TP53 in response to DNA damage. We identify a role for TP63 in transcriptional regulation of multiple genes genetically linked to cleft palate and identify AP-2alpha (TFAP2A) as a co-regulator of a subset of these genes. We further demonstrate that AP-2gamma (TFAP2C) can bind a subset of these regions and that acute depletion of either TFAP2A or TFAP2C alone is sufficient to reduce terminal differentiation of organotypic epidermal skin equivalents, indicating overlapping physiological functions with TP63.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>22573176</pmid><doi>10.1093/nar/gks389</doi><tpages>17</tpages><oa>free_for_read</oa></addata></record> |
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subjects | AP-2 protein Binding Sites Cell Differentiation Cells, Cultured Chromatin Cleft lip/palate Cleft Palate - genetics Differentiation DNA damage Epidermal Cells Gene Expression Regulation Gene regulation Gene Regulation, Chromatin and Epigenetics Genome, Human Genomes Humans Immunoprecipitation Keratinocytes Keratinocytes - cytology Keratinocytes - metabolism Molecular Sequence Annotation Mutation Neonates Neoplasia p53 protein Regulatory Elements, Transcriptional Skin Transcription Transcription Factor AP-2 - antagonists & inhibitors Transcription Factor AP-2 - metabolism Transcription factors Transcription Factors - metabolism Tumor Suppressor Protein p53 - metabolism Tumor Suppressor Proteins - metabolism |
title | Genome-wide analysis of p63 binding sites identifies AP-2 factors as co-regulators of epidermal differentiation |
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