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Loss of the C-terminus of p63 leads to an increased binding of p63 to promoters and histone acetylation [ChIP-seq]

ABSTRACT: The transcription factor p63 is a master gene of epithelial development. p63 regulates expression of genes related to proliferation, differentiation and adhesion by binding epithelial enhancers. Biochemically, p63 interacts with chromatin via its DNA binding domain, while N-terminus is essential for the fine tuning of its transcriptional activity. However, the role of the C-terminus of p63 remains elusive. Here, we investigate the role of the C-terminal SAM domain of p63 in vivo. We generated Krt14-specific knock-out of the SAM domain (exon 13) of p63 which resulted in expression of the p63b isoform. Most of p63b expressing mice die 2-3 months after birth and show alteration of skin, adipose tissue and muscle morphology. Mechanistically, ChIP-seq analysis showed an increased binding of p63b to gene promoters. Further integration of transcriptome and genome occupancy analyses revealed that p63b binds more readily promoter regions of extracellular matrix (ECM) genes leading to their enhanced expression. Aberrant expression of ECM genes by p63b disrupts normal adhesion of keratinocytes to basal lamina triggering systemic inflammation and premature death. Altogether, our data suggest that C-terminus ensures p63 selectivity in enhancer binding to maintain physiological levels of extracellular matrix and adhesion proteins.

ORGANISM(S): Mus musculus

PROVIDER: GSE241105 | GEO | 2025/07/22

REPOSITORIES: GEO

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Loss of the C-terminus of p63 leads to an increased expression of extracellular matrix genes in keratinocytes [RNA-seq]

Project description:The transcription factor p63 is a master gene of epithelial development. p63 regulates expression of genes related to proliferation, differentiation and adhesion by binding epithelial enhancers. Biochemically, p63 interacts with chromatin via its DNA binding domain, while N-terminus is essential for the fine tuning of its transcriptional activity. However, the role of the C-terminus of p63 remains elusive. Here, we investigate the role of the C-terminal SAM domain of p63 in vivo. We generated Krt14-specific knock-out of the SAM domain (exon 13) of p63 which resulted in expression of the p63b isoform. Most of p63b expressing mice die 2-3 months after birth and show alteration of skin, adipose tissue and muscle morphology. Mechanistically, ChIP-seq analysis showed an increased binding of p63b to gene promoters. Further integration of transcriptome and genome occupancy analyses revealed that p63b binds more readily promoter regions of extracellular matrix (ECM) genes leading to their enhanced expression. Aberrant expression of ECM genes by p63b disrupts normal adhesion of keratinocytes to basal lamina triggering systemic inflammation and premature death. Altogether, our data suggest that C-terminus ensures p63 selectivity in enhancer binding to maintain physiological levels of extracellular matrix and adhesion proteins.

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Loss of the C-terminus of p63 leads to an increased expression of extracellular matrix genes in keratinocytes due to a preferential binding of p63 to promoters

Project description:Loss of the C-terminus of p63 leads to an increased expression of extracellular matrix genes in keratinocytes due to a preferential binding of p63 to promoters

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shRNA human ME180 cells depleted for p63 versus wildtype ME180 cells

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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>

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Project description: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.

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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.

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