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Novel p63 target genes involved in paracrine signaling and keratinocyte differentiation.

ABSTRACT: The transcription factor p63 is required for proper epidermal barrier formation and maintenance. Herein, we used chromatin immunoprecipitation coupled with DNA sequencing to identify novel p63 target genes involved in normal human epidermal keratinocyte (NHEKs) growth and differentiation. We identified over 2000 genomic sites bound by p63, of which 82 were also transcriptionally regulated by p63 in NHEKs. Through the discovery of interleukin-1-α as a p63 target gene, we identified that p63 is a regulator of epithelial-mesenchymal crosstalk. Further, three-dimensional organotypic co-cultures revealed TCF7L1, another novel p63 target gene, as a regulator of epidermal proliferation and differentiation, providing a mechanism by which p63 maintains the proliferative potential of basal epidermal cells. The discovery of new target genes links p63 to diverse signaling pathways required for epidermal development, including regulation of paracrine signaling to proliferative potential. Further mechanistic insight into p63 regulation of epidermal cell growth and differentiation is provided by the identification of a number of novel p63 target genes in this study.

SUBMITTER: Barton CE

PROVIDER: S-EPMC3000738 | biostudies-literature | 2010

REPOSITORIES: biostudies-literature

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Novel p63 target genes involved in paracrine signaling and keratinocyte differentiation.

Barton C E CE Johnson K N KN Mays D M DM Boehnke K K Shyr Y Y Boukamp P P Pietenpol J A JA

Cell death & disease 20100101

The transcription factor p63 is required for proper epidermal barrier formation and maintenance. Herein, we used chromatin immunoprecipitation coupled with DNA sequencing to identify novel p63 target genes involved in normal human epidermal keratinocyte (NHEKs) growth and differentiation. We identified over 2000 genomic sites bound by p63, of which 82 were also transcriptionally regulated by p63 in NHEKs. Through the discovery of interleukin-1-α as a p63 target gene, we identified that p63 is a ...[more]

PMID: 21151771

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Project description:Epidermal homeostasis relies on a well-defined transcriptional control of keratinocyte proliferation and differentiation, which is critical to prevent skin diseases such as atopic dermatitis, psoriasis or cancer. We have recently shown that the homeobox transcription factor DLX3 and the tumor suppressor p53 co-regulate cell cycle-related signaling and that this mechanism is functionally involved in cutaneous squamous cell carcinoma development. Here we show that DLX3 expression and its downstream signaling depend on protein kinase C α (PKCα) activity in skin. We found that following 12-O-tetradecanoyl-phorbol-13-acetate (TPA) topical treatment, DLX3 expression is significantly upregulated in the epidermis and keratinocytes from mice overexpressing PKCα by transgenic targeting (K5-PKCα), resulting in cell cycle block and terminal differentiation. Epidermis lacking DLX3 (DLX3cKO), which is linked to the development of a DLX3-dependent epidermal hyperplasia with hyperkeratosis and dermal leukocyte recruitment, displays enhanced PKCα activation, suggesting a feedback regulation of DLX3 and PKCα. Of particular significance, transcriptional activation of epidermal barrier, antimicrobial peptide and cytokine genes is significantly increased in DLX3cKO skin and further increased by TPA-dependent PKC activation. Furthermore, when inhibiting PKC activity, we show that epidermal thickness, keratinocyte proliferation and inflammatory cell infiltration are reduced and the PKC-DLX3-dependent gene expression signature is normalized. Independently of PKC, DLX3 expression specifically modulates regulatory networks such as Wnt signaling, phosphatase activity and cell adhesion. Chromatin immunoprecipitation sequencing analysis of primary suprabasal keratinocytes showed binding of DLX3 to the proximal promoter regions of genes associated with cell cycle regulation, and of structural proteins and transcription factors involved in epidermal differentiation. These results indicate that Dlx3 potentially regulates a set of crucial genes necessary during the epidermal differentiation process. Altogether, we demonstrate the existence of a robust DLX3-PKCα signaling pathway in keratinocytes that is crucial to epidermal differentiation control and cutaneous homeostasis.

Project description:BackgroundMelanoma is the deadliest type of skin cancer. Until now, its pathological mechanisms, particularly the mechanism of metastasis, remain largely unknown. Our study on the identification of genes in association with metastasis for melanoma provides a novel understanding of melanoma.MethodsFrom the Gene Expression Omnibus (GEO) database, the gene expression microarray datasets GSE46517, GSE7553, and GSE8401 were downloaded. We made use of R aiming at analyzing the differentially expressed genes (DEGs) between metastatic and nonmetastatic melanoma. R was also used in differentially expressed miRNA (DEM) data mining from GSE18509, GSE19387, GSE24996, GSE34460, GSE35579, GSE36236, and GSE54492 datasets referring to Li's study. Based on the DEG and DEM data, we performed functional enrichment analysis through the application of the DAVID database. Furthermore, we constructed the protein-protein interaction (PPI) network and established functional modules by making use of the STRING database. Through making use of Cytoscape, the PPI results were visualized. We predicted the targets of the DEMs through applying TargetScan, miRanda, and PITA databases and identified the overlapping genes between DEGs and predicted targets, followed by the construction of DEM-DEG pair network. The expressions of these keratinocyte differentiation-involved genes in Module 1 were identified based on the data from TCGA.Results239 DEGs were screened out in all 3 datasets, which were inclusive of 21 positively regulated genes and 218 negatively regulated genes. Based on these 239 DEGs, we finished constructing the PPI network which was formed from 225 nodes and 846 edges. We finished establishing 3 functional modules. And we analyzed 92 overlapping genes and 26 miRNA, including 11 upregulated genes targeted by 11 negatively regulated DEMs and 81 downregulated genes targeted by 15 positively regulated DEMs. As proof of the differential expression of metastasis-associated genes, eleven keratinocyte differentiation-involved genes, including LOR, EVPL, SPRR1A, FLG, SPRR1B, SPRR2B, TGM1, DSP, CSTA, CDSN, and IVL in Module 1, were obviously downregulated in metastatic melanoma tissue in comparison with primary melanoma tissue based on the data from TCGA.Conclusion239 melanoma metastasis-associated genes and 26 differentially expressed miRNA were identified in our study. The keratinocyte differentiation-involved genes may take part in melanoma metastasis, providing a latent molecular mechanism for this disease.

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Novel p63 target genes involved in paracrine signaling and keratinocyte differentiation.

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Novel p63 target genes involved in paracrine signaling and keratinocyte differentiation.

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