Genome-wide p63-Target Gene Analyses Reveal TAp63/NRF2-Dependent Oxidative Stress Responses

The p53 family member TP63 encodes two sets of N-terminal isoforms, TAp63 and Delta Np63 isoforms. They each regulate diverse biological functions in epidermal morphogenesis and in cancer. In the skin, where their activities have been extensively characterized, TAp63 prevents premature aging by regulating the quiescence and genomic stability of stem cells required for wound healing and hair regeneration, while Delta Np63 controls maintenance and terminal differentiation of epidermal basal cells. This functional diversity is surprising given that these isoforms share a high degree of similarity, including an identical sequence for a DNA-binding domain. To understand the mechanisms of the transcriptional programs regulated by each p63 isoform and leading to diverse biological functions, we performed genome-wide analyses using p63 isoform-specific chromatin immunoprecipitation, RNA sequencing, and metabolomics of TAp63-/- and Delta Np63-/- mouse epidermal cells. Our data indicate that TAp63 and Delta Np63 physically and functionally interact with distinct transcription factors for the downstream regulation of their target genes, thus ultimately leading to the regulation of unique transcriptional programs and biological processes. Our findings unveil novel transcriptomes regulated by the p63 isoforms to control diverse biological functions, including the cooperation between TAp63 and NRF2 in the modulation of metabolic pathways and response to oxidative stress providing a mechanistic explanation for the TAp63 knock out phenotypes.Significance: The p63 isoforms, TAp63 and Delta Np63, control epithelial morphogenesis and tumorigenesis through the interaction with distinct transcription factors and the subsequent regulation of unique transcriptional programs.