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Chromatin modification is not a prerequisite for p63 binding but p63 binding can elicit chromatin remodeling

ABSTRACT: Transcription factor (TF) p63 is a master regulator playing critical roles in epidermal development and other cellular processes. Our lab’s previous research deciphered a distinct chromatin architecture at p63 bound site in keratinocytes. In order to figure out whether those chromatin modifications already exist before p63 binding, or p63 occupancy contributes to such chromatin marks, we built p63-expressing cell lines. We then obtained p63 bound regions in these overexpressing cell line, and looked at different histone marks at those sites before p63 occupancy. As shown in the results, before p63 binding, the targeting sites have barely detectable histone marks, indicating p63’s capability to approach unmodified chromatins. Moreover, there is no significant difference in chromatin marks between p63 bound sites and unbound sites when no p63 binding happens. Our in vivo findings were confirmed by examining p63 binding to unmodified nucleosomes in vitro, showing that histone modification is not indispensable for p63 binding but binding site positioning on nucleosome does play a role. Overall, our results suggest that histone modifications do not affect p63 binding, and p63 protein can bind to inaccessible, weakly modified chromatin regions in vivo.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140329 | GEO | 2020/12/01

REPOSITORIES: GEO

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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>

| phs001737 | dbGaP

BAF controls genome accessibility

Project description:Somatic differentiation requires induction of lineage specific genes to fulfill specialized tissue functions yet the genomic control of this process is incompletely understood. Using the epidermis as a model, we show here that the BAF chromatin remodeling complex is essential to maintain a subset of open chromatin regions, which are strikingly enriched for the DNA binding motif of the stratified epithelial lineage-determining transcription factor p63 (p=1X10-1786). These p63 sites are intrinsically inaccessible. BAF is required to displace nucleosomes ~40 base pairs away from p63 motifs to enable p63 binding, to maintain active histone marks, and to recruit RNA polymerase II to promote gene expression. In this process, p63 was itself also essential for full BAF recruitment to p63 binding sites. Intrinsically, p63 binding sequences favor nucleosome occupancy. Our data therefore suggest a model where a lineage-specific transcription factor cooperates with the BAF complex to establish genome accessibility and engage tissue-specific gene expression.

2015-11-12 | GSE67382 | GEO

Genome-wide profiling of p63 binding sites identifies genes and regulatory elements for p63-related disorders

Project description:We identified p63 target genes and binding sites responsible for ectodermal defects by genome-wide profiling of p63 binding using ChIP-seq and expression analysis in human primary keratinocytes from patients with p63 mutations. As proof of principle, we identified a novel de novo microdeletion causing limb defects (SHFM1) that includes a p63 binding site functioning as a cis-regulatory element to control expression of the distally located DLX5/DLX6 genes essential for limb development. Our data demonstrate that target genes and regulatory elements detected in this study can serve as powerful tools to identify causative mutations of unresolved ectodermal disorders. ChIP-seq profiles of p63 in primary human keratinocytes established from two different normal individuals.

2010-08-15 | E-GEOD-17611 | biostudies-arrayexpress

p63 ChIP-seq analysis comparing WT, TAp63-null, and DNp63-null primary murine keratinocytes

Project description:We performed a ChIP-seq analysis characterizing the p63 binding sites in primary keratinocytes obtained from E18.5 mice of 3 different genotypes (WT, TAp63-/-, and ΔNp63-/-). We aimed to identify the specific genomic regions bound by TAp63 and ΔNp63 in physiological conditions.

2018-03-20 | GSE79448 | GEO

Chromatin modification is not a prerequisite for p63 binding but p63 binding can elicit chromatin remodeling

Project description:Chromatin modification is not a prerequisite for p63 binding but p63 binding can elicit chromatin remodeling

| PRJNA589301 | ENA

Genome-wide profiling of p63 binding sites identifies genes and regulatory elements for p63-related disorders

2010-08-15 | GSE17611 | GEO

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

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

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 | E-GEOD-59824 | biostudies-arrayexpress

Genome-wide transcription factor binding and histone mark profiling in pluripotent and lineage-committed cells

Project description:Purpose: Assess changes in p63 binding in human embryonic stem cells and surface ectoderm; evaluate differences in the following histone marks: H3K27me3, H3K27ac, H3K4me1, and H3K4me3 in the surface ectoderm with and without p63; and examine changes in H3K27me3 between human embyronic stem cells and surface ectoderm with and without p63. Methods: p63 ChIP-seq libraries were generated in p63 gain-of-function human embryonic stem cells and wild-type surface ectoderm. H3K27me3 ChIP-seq libraries were generated in wild-type and p63 gain-of-function human embryonic stem cells as well as wild-type and p63 knockout surface ectoderm. H3K27ac, H3K4me1, and H3K4me3 ChIP-seq libraries were generated in wild-type and p63 knockout surface ectoderm. All ChIP-seq experiments were performed in duplicate and sequenced on Illumina NextSeq 500 sequencer. To ensure quality reads, fastq files were analyzed using FASTQC. Bowtie was used for read mapping and the parameters were as follows: -p 24 -S -a -m 1 --best --strata. For peak calling using MACS2, default settings were specified with a p-value of 0.05. To ensure quality peaks, IDR was run on all files, specifying FDR of 1% or 5% (or 10% for some broadPeak histone marks). Results: Limited changes in p63 binding in human embryonic stem cells and surface ectoderm; global loss of H3K37me3 without p63 in the surface ectoderm; limited differences in H3K27ac, H3K4me1, and H3K4me3 +/- p63 in the surface ectoderm; and increase in H3K27me3 with ectopic expression of p63 in human embryonic stem cells. Conclusion: p63 is able to bind it's surface ectoderm target sites regardless of the epigenetic landscape; p63 promotes H3K27me3 accumulation; and p63 does not regulate histone marks H3K27ac, H3K4me1, or H3K4me3

2018-11-06 | GSE122128 | GEO

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