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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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE241232 | GEO | 2025/07/22
REPOSITORIES: GEO
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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.
2025-07-22 | GSE241109 | GEO
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
| PRJNA1006762 | ENA
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.
2025-07-22 | GSE241105 | GEO
Project description:Here, we investigated the potential interaction between bromodomain-containing protein 4 (BRD4), an established epigenetic modulator and transcriptional coactivator, and p63, a member of the p53 transcription factor family, essential for epithelial development and skin homeostasis. Our protein-protein interaction assays demonstrated a strong and conserved physical interaction between BRD4 and the p53 family members-p63, p73, and p53-suggesting a shared binding region among these proteins. While the role of BRD4 in cancer development through its interaction with p53 has been explored, the effects of BRD4 and Bromodomain and Extra Terminal (BET) inhibitors in non-transformed cells, such as keratinocytes, remain largely unknown. Our functional analyses revealed changes in cellular proliferation and differentiation in keratinocytes depleted of either p63 or BRD4, which were further supported by using the BRD4 inhibitor JQ1. Transcriptomic analyses, chromatin immunoprecipitation, and RT-qPCR indicated a synergistic mechanism between p63 and BRD4 in regulating the transcription of keratinocyte-specific p63 target genes, including HK2, FOXM1, and EVPL. This study not only highlights the complex relationship between BRD4 and p53 family members but also suggests a role for BRD4 in maintaining keratinocyte functions. Our findings pave the way for further exploration of potential therapeutic applications of BRD4 inhibitors in treating skin disorders.
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Project description:p63 is a transcription factor required for the development and maintenance of ectodermal tissues in general, and skin keratinocytes in particular. The identification of its target genes is fundamental for understanding the complex network of gene regulation governing the development of epithelia. We report a list of almost 1000 targets derived from ChIP on chip analysis on two platforms; all genes analyzed changed in expression during differentiation of human keratinocytes. Functional annotation highlighted unexpected GO terms enrichments and confirmed that genes involved in transcriptional regulation are the most significant. A detailed analysis of these transcriptional regulators in condition of perturbed p63 levels confirmed the role of p63 in the regulatory network. Rather than a rigid master-slave hierarchical model, our data indicate that p63 connects different hubs involved in the multiple specific functions of the skin.
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Project description:Increased synthesis and deposition of extracellular matrix (ECM) proteins in the trabecular meshwork (TM) is associated with TM dysfunction and intraocular pressure (IOP) elevation in glaucoma. However, it is not understood how ECM accumulation leads to TM dysfunction and IOP elevation. Using a mouse model of glucocorticoid (GC)-induced glaucoma, primary human TM cells and human post-mortem TM tissues, we show that increased ECM accumulation leads to endoplasmic reticulum (ER) stress in the TM. The potent GC, dexamethasone (Dex) increased the secretory protein load of ECM proteins in the ER of TM cells, inducing ER stress. Reduction of fibronectin, a major regulator of ECM structure, prevented ER stress in Dex-treated TM cells. Overexpression of fibronectin via treatment with cellular fibronectin also induced chronic ER stress in primary human TM cells. Primary human TM cells grown on ECM derived from Dex-treated TM cells induced ER stress markers. TM cells were more prone to ER stress from ECM accumulation compared to other ocular cell types. Moreover, increased co-localization of ECM proteins with ER stress markers was observed in human post-mortem glaucomatous TM tissues. These data indicate that ER stress is associated with increased ECM accumulation in mouse and human glaucomatous TM tissues.
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Project description:Osteonecrosis of the jaw (ONJ), a side-effect of bisphosphonate therapy, is characterized by exposed bone that fails to heal within eight weeks. Healing time of oral epithelial wounds is decreased in the presence of amino-bisphosphonates; however, the mechanism remains unknown. We examined human tissue from individuals with ONJ and non-bisphosphonate-treated control individuals to identify changes in oral epithelium and connective tissue. Oral and intravenous bisphosphonate-treated ONJ sites had reduced numbers of basal epithelial progenitor cells, as demonstrated by a 13.8±1.1% and 31.9±5.8% reduction of p63 expression, respectively. No significant differences in proliferation rates, vessel density, or macrophage number were noted. In vitro treatment of clonal and primary oral keratinocytes with zoledronic acid (ZA) inhibited p63, and expression was rescued by the addition of mevalonate pathway intermediates. In addition, both ZA treatment and p63 shRNA knock-down impaired formation of 3D Ex Vivo Produced Oral Mucosa Equivalents (EVPOME) and closure of an in vitro scratch assay. Analysis of our data suggests that bisphosphonate treatment may delay oral epithelial healing by interfering with p63-positive progenitor cells in the basal layer of the oral epithelium in a mevalonate-pathway-dependent manner. This delay in healing may increase the likelihood of osteonecrosis developing in already-compromised bone.
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Project description:The extracellular matrix (ECM) is a major component of tumors and a significant contributor to cancer progression. In this study, we use proteomics to investigate the ECM of human mammary carcinoma xenografts and show that primary tumors of differing metastatic potential differ in ECM composition. Both tumor cells and stromal cells contribute to the tumor matrix and tumors of differing metastatic ability differ in both tumor- and stroma-derived ECM components. We define ECM signatures of poorly and highly metastatic mammary carcinomas and these signatures reveal up-regulation of signaling pathways including TGF? and VEGF. We further demonstrate that several proteins characteristic of highly metastatic tumors (LTBP3, SNED1, EGLN1, and S100A2) play causal roles in metastasis, albeit at different steps. Finally we show that high expression of LTBP3 and SNED1 correlates with poor outcome for ER(-)/PR(-)breast cancer patients. This study thus identifies novel biomarkers that may serve as prognostic and diagnostic tools. DOI: http://dx.doi.org/10.7554/eLife.01308.001.
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Project description:The transcription factor p63 is a key regulator in epidermal keratinocyte proliferation and differentiation. However, the role of p63 in gene regulation during these processes is not well understood. To investigate this, we recently generated genome-wide profiles of gene expression, p63 binding sites and active regulatory regions with the H3K27ac histone mark (Kouwenhoven et al., 2015). We showed that only a subset of p63 binding sites are active in keratinocytes, and that differentiation-associated gene expression dynamics correlate with the activity of p63 binding sites rather than with their occurrence per se. Here we describe in detail the generation and processing of the ChIP-seq and RNA-seq datasets used in this study. These data sets are deposited in the Gene Expression Omnibus (GEO) repository under the accession number GSE59827.
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Project description:The transcription factor p63 mediates distinct cellular responses, primarily regulating epithelial and oocyte biology. In addition to the two amino terminal isoforms, TAp63 and ΔNp63, the 3'-end of p63 mRNA undergoes tissue-specific alternative splicing that leads to several isoforms, including p63α, p63β and p63γ. To investigate in vivo how the different isoforms fulfil distinct functions at the cellular and developmental levels, we developed a mouse model replacing the p63α with p63β by deletion of exon 13 in the Trp63 gene. Here, we report that whereas in two organs physiologically expressing p63α, such as thymus and skin, no abnormalities are detected, total infertility is evident in heterozygous female mice. A sharp reduction in the number of primary oocytes during the first week after birth occurs as a consequence of the enhanced expression of the pro-apoptotic transcriptional targets Puma and Noxa by the tetrameric, constitutively active, TAp63β isoform. Hence, these mice show a condition of ovary dysfunction, resembling human primary ovary insufficiency. Our results show that the p63 C-terminus is essential in TAp63α-expressing primary oocytes to control cell death in vivo, expanding the current understanding of human primary ovarian insufficiency.
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