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Transcription factor p63 bookmarks genomic loci in epithelial cells and regulates a subset of target genes during epidermal differentiation through dynamic enhancers (ChIP-Seq)

ABSTRACT: Tightly controlled gene expression orchestrated by the transcription factor p63 during epithelial differentiation is important for development of epithelial-related structures such as epidermis, limb and craniofacial regions. How p63 regulates spatial and temporal expression of its target genes during these developmental processes is however not yet clear. By epigenomics profiling in stem cells established from one of these epithelial structures, the epidermis, we provide a global map of p63-bound regulatory elements that are categorized as single enhancers and clustered enhancers during epidermal differentiation. Transcriptomics analysis shows dynamic gene expression patterns during epidermal differentiation that correlates with the activity of p63-bound enhancers rather than with p63 binding itself. Only a subset of p63-bound enhancers is active in epidermal stem cells, and inactive p63-bound enhancers appear to function in gene regulation during the development of other epithelial tissues. Our data suggest a paradigm that p63 bookmarks genomic loci during the commitment of the epithelial lineage and regulates gene expression in different epithelial tissues through tissue-specific active enhancers. The catalogue of differentially expressed epidermal genes including non-coding RNAs and epithelial enhancers reported here provides a rich resource for studies of epithelial development and related diseases. Different stages of keratinocyte differentiation

ORGANISM(S): Homo sapiens

SUBMITTER: Jo Huiqing Zhou

PROVIDER: E-GEOD-59824 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcription factor p63 bookmarks genomic loci in epithelial cells and regulates a subset of target genes during epidermal differentiation through dynamic enhancers (RNA-Seq)

Project description:Tightly controlled gene expression orchestrated by the transcription factor p63 during epithelial differentiation is important for development of epithelial-related structures such as epidermis, limb and craniofacial regions. How p63 regulates spatial and temporal expression of its target genes during these developmental processes is however not yet clear. By epigenomics profiling in stem cells established from one of these epithelial structures, the epidermis, we provide a global map of p63-bound regulatory elements that are categorized as single enhancers and clustered enhancers during epidermal differentiation. Transcriptomics analysis shows dynamic gene expression patterns during epidermal differentiation that correlates with the activity of p63-bound enhancers rather than with p63 binding itself. Only a subset of p63-bound enhancers is active in epidermal stem cells, and inactive p63-bound enhancers appear to function in gene regulation during the development of other epithelial tissues. Our data suggest a paradigm that p63 bookmarks genomic loci during the commitment of the epithelial lineage and regulates gene expression in different epithelial tissues through tissue-specific active enhancers. The catalogue of differentially expressed epidermal genes including non-coding RNAs and epithelial enhancers reported here provides a rich resource for studies of epithelial development and related diseases. Comparison of gene expression at different stages of keratinocyte differentiation

2015-05-01 | E-GEOD-59822 | biostudies-arrayexpress

Genome wide identification of p63 binding sites in human neonatal foreskin keratinocytes

Project description:We report here genome wide identification of p63 binding sites in cycling neonatal foreskin keratinocytes using high throughput sequencing of ChIP enriched DNA. Analysis of gene ontology, database mining with integration with publicly available data, reveals a role for p63 in transcriptional regulation of multiple genes genetically linked to cleft palate. In addition, we identify AP-2Î±, a transcription factor which, when mutated, also results in craniofacial clefting syndrome, as a co-regulator of p63 responsive genes. Examination of p63 binding sites in neonatal foreskin keratinocytes

2012-06-07 | E-GEOD-32061 | biostudies-arrayexpress

TP63 regulation of epithelial to mesenchymal transition in an experimental prostate cell model

Project description:p63 is a transcription factor central for epithelial homeostasis and development. In our model of epithelial to mesenchymal transition (EMT) in a human prostate cell culture model, p63 was one of the most down-regulated transcription factors during EMT. We therefore investigated the role of p63 in EMT by a gain and loss of function approach. Over-expression of the predominant epithelial isoform DNp63a in mesenchymal EPT1B8 cells led to gain of several epithelial characteristics without resulting in a complete mesenchymal to epithelial transition (MET). This was corroborated by a reciprocal effect when p63 was knocked down in epithelial EP156T cells. Global gene expression analyses found that DNp63a induced gene modules involving cell adhesion genes in mesenchymal like cells. Genome-wide analysis of p63 binding sites by ChIP-seq analyses confirmed binding of p63 to regulatory areas of genes associated with cell adhesion in prostate epithelial cells.CDH1 and ZEB1 are two elemental factors in the control of EMT. Over-expression and knock-down of these factors, respectively, were not sufficient alone or in combination with DNp63a to reverse the mesenchymal phenotype in EPT1 cells. The partial reversion of epithelial to mesenchymal transition might reflect the ability of DNp63a, as a key co-ordinator of several epithelial gene expression modules, to reduce epithelial to mesenchymal plasticity (EMP). The utility of DNp63a expression and the potential of reduced EMP in order to counteract metastasis warrant further investigation. Examination of p63 binding profile in prostate cell model EP156T with EPT1 as negative control.

2013-12-20 | E-GEOD-43111 | biostudies-arrayexpress

Transcription factor p63 bookmarks genomic loci in epithelial cells and regulates a subset of target genes during epidermal differentiation through dynamic enhancers (RNA-Seq)

2015-05-01 | GSE59822 | GEO

Transcription factor p63 bookmarks genomic loci in epithelial cells and regulates a subset of target genes during epidermal differentiation through dynamic enhancers (ChIP-Seq)

2015-05-01 | GSE59824 | GEO

Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape

Project description:<p>Transcription factor p63 is a key regulator of epidermal keratinocyte proliferation and differentiation. Mutations in the p63 DNA-binding domain are associated with Ectrodactyly Ectodermal Dysplasia Cleft Lip/Palate (EEC) syndrome. Underlying molecular mechanism of these mutations however remain unclear. Here we characterized the transcriptome and epigenome of p63 mutant keratinocytes derived from EEC patients. The transcriptome of p63 mutant keratinocytes deviated from the normal epidermal cell identity. Epigenomic analyses showed an altered enhancer landscape in p63 mutant keratinocytes contributed by loss of p63-bound active enhancers and by unexpected gain of enhancers. The gained enhancers were frequently bound by deregulated transcription factors such as RUNX1. Reversing RUNX1 overexpression partially rescued deregulated gene expression and the altered enhancer landscape. Our findings identify an unreported disease mechanism whereby mutant p63 rewires the enhancer landscape and affects epidermal cell identity, consolidating the pivotal role of p63 in controlling the enhancer landscape of epidermal keratinocytes.</p>

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Disrupted transcriptional network in ΔNp63 AEC tissue model [ChIP-Seq]

Project description:The transcriptional basis for disrupted epidermal differentiation arising from TP63 AEC mutations remains to be elucidated. Here we present an organotypic model of AEC dysfunction that phenocopies differentiation defects observed in AEC patient skin. Transcriptional analysis of model AEC tissue revealed impaired induction of differentiation regulators, including OVOL1, GRHL3, KLF4, PRDM1 and ZNF750. Genome wide binding analyses of TP63 during epidermal differentiation showed direct binding of OVOL1, GRHL3, and ZNF750 promoters suggesting AEC mutants prevent normal activation of these targets by direct transcriptional interference. Remarkably, exogenous ZNF750 restores impaired epidermal differentiation caused by AEC mutation. Thus, repression of ZNF750 is central to disrupted epidermal differentiation in model AEC tissue. ChIP-Seq analysis: Examination of p63 binding in proliferating and differentiating human keratinocytes

2012-06-18 | E-GEOD-33571 | biostudies-arrayexpress

ChIP seq for p63, H3K27ac and BRD4 in L3.6pl, BxPC-3 pancreatic cancer cell lines and ChIP-seq of H3K27ac and BRD4 in Panc-1 pancreatic cell line

Project description:We investigated the regions that are occupied by deltaNp63 in BxPC-3 and L3.6pl and identification of super enhancers in different pancreatic cancer cell lines. Thereby, we identified a group of 45 super enhancers that are associated with poorer prognosis and are highly dependent on deltaNp63.

2018-12-18 | E-MTAB-7034 | biostudies-arrayexpress

Genome wide characterization reveals complex interplay between TP53 and TP63 in response to genotoxic stress [ChIP-Seq]

Project description:In response to genotoxic stress the TP53 tumour suppressor activates target gene expression to induce cell cycle arrest or apoptosis depending on the extent of DNA damage. These canonical activities can be repressed by TP63 in normal stratifying epithelia to maintain proliferative capacity or drive proliferation of squamous cell carcinomas, where TP63 is frequently overexpressed/amplified. Here we use ChIP-sequencing, integrated with microarray analysis, to define the genome wide interplay between TP53 and TP63 in response to genotoxic stress in normal cells. We reveal that TP53 and TP63 bind to overlapping, but distinct cistromes of sites through utilization of distinctive consensus motifs and that TP53 is constitutively bound to a number of sites. We demonstrate that cisplatin and adriamycin elicit distinct effects on TP53 and TP63 binding events, through which TP53 can induce or repress transcription of an extensive network of genes by direct binding and/or modulation of TP63 activity. Collectively, this results in a global TP53 dependent repression of cell cycle progression, mitosis and DNA damage repair concomitant with activation of anti-proliferative and pro-apoptotic canonical target genes. Further analyses reveals that in the absence of genotoxic stress TP63 plays an important role in maintaining expression of DNA repair genes, loss of which results in defective repair Examination of p63 and p53 binding sites in neonatal foreskin keratinocytes in response to adriamycin or cisplatin treatment

2014-04-11 | E-GEOD-56674 | biostudies-arrayexpress

Mutant p63 disrupts the key specification switch from the multipotent cell state to stratified epithelia during epithelial differentiation/in ectodermal dysplasia disorders

Project description:Transcription factor p63 is a key regulator of stratified epithelia. In humans mutations in p63 are associated with developmental disorders that manifest defects in stratified epithelia including the epidermis. We established an epidermal commitment model using human pluripotent stem cells (PSCs) and characterized differentiation defects of PSCs carrying p63 mutations. Transcriptome analyses revealed distinct phases of epidermal commitment, multipotent simple epithelial, basal stratified epithelial and mature epidermal fates. Differentiation defects of p63 mutant PSCs occurred during the specification switch from the simple epithelium to the basal stratified epithelial fate. Single-cell transcriptome and pseudotime analyses identified enhanced mesodermal signatures associated with the deviated commitment route of p63 mutant PSCs. Repressing mesodermal differentiation improved epidermal commitment of PSCs. Our study demonstrate that p63 is required for specification of stratified epithelia but not sufficient for epidermal maturation. It provides insights into disease mechanisms underlying defects of stratified epithelia caused by p63 mutations.

2019-08-19 | GSE120107 | GEO

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