Hdac1 and Hdac2 Act Redundantly to Control p63 and p53 Functions in Epidermal Progenitor Cells

Abstract

Summary Epidermal and hair follicle development from surface ectodermal progenitor cells require coordinated changes in gene expression. Histone deacetylases alter gene expression programs through modification of chromatin and transcription factors. We find that deletion of ectodermal Hdac1 and Hdac2 results in dramatic failure of hair follicle specification and epidermal proliferation and stratification, phenocopying loss of the key ectodermal transcription factor p63. While expression of p63 and its positively regulated basal cell targets is maintained in Hdac1/2 deficient ectoderm, targets of p63-mediated repression, including p21, 14-3-3σ and p16/INK4a, are ectopically expressed, and HDACs bind and are active at their promoter regions in normal undifferentiated keratinocytes. Mutant embryos display increased levels of acetylated p53, which opposes p63 functions, and p53 is required for HDAC inhibitor-mediated p21 expression in keratinocytes. Our data identify critical requirements for HDAC1/2 in epidermal development, and indicate that HDAC1/2 directly mediate repressive functions of p63, and suppress p53 activity.

p53/p63/p73 in the Epidermis in Health and Disease

“…DNp63 also cooperates with HDAC1/2 to directly repress p16/INK4a in epidermal keratinocytes, whereas HDAC1/2 independently deacetylate p53 and suppress its ability to induce apoptosis and activate target genes, including p21 (LeBoeuf et al 2010). Conversely, p63 gene expression in epidermal keratinocytes is positively regulated by the histone methyltransferase Setd8, as well as by the DEC1 transcription factor (Driskell et al 2011;Qian et al 2011).…”

“…The p63 isoforms play distinct roles in the control of epidermal development; the DNp63 isoforms are much more abundant in the epidermis compared to TAp63, which is strongly expressed in basal epidermal keratinocytes and is markedly down-regulated in the spinous epidermal layer (Laurikkala et al 2006;Romano et al 2009Romano et al , 2012LeBoeuf et al 2010;Shalom-Feuerstein et al 2011). TAp63 is also expressed in response to stresses such as wound healing (Su et al 2009b).…”

HDAC1 and HDAC2 in mouse oocytes and preimplantation embryos: Specificity versus compensation

“…Indeed, loss-of-function studies in mice provide important insights regarding the compensatory functions of HDAC1 and HDAC2 in regulating cell proliferation, apoptosis, and differentiation in different cell types and tissues. 8,28 Tissue-specific conditional knockout of Hdac1 or Hdac2 alone does not evoke an obvious phenotype in cardiomyocytes, 29 neuron precursors, 30 oligodendrocyte, 31 B cells, 32 embryonic epidermis, 33 and T cells, 34 whereas deletion of both genes results in severe phenotypes in all tissues examined. In contrast, results of other studies support the notion that HDAC1 and HDAC2 have distinct functions.…”

Phospho-ΔNp63α is a key regulator of the cisplatin-induced microRNAome in cancer cells

“…[27][28][29][30][31][32] Recent report showed that HDAC1/2 are present at the promoter regions of DNp63-repressed targets in keratinocytes, indicating a direct requirement for HDAC1/2 in DNp63-mediated repression. 39 Materials and Methods Cells and reagents. TheHNSCC cell line JHU-029 (expressing wild-type p53 and p63) was isolated from primary tissue at the Department of Otolaryngology/ Head and Neck Surgery of the Johns Hopkins University School of Medicine.…”