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
Hauptverfasser: 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
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container_end_page 7206
container_issue 15
container_start_page 7190
container_title Nucleic acids research
container_volume 40
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.
doi_str_mv 10.1093/nar/gks389
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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 &gt;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. 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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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