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

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.