Delta Np63-Senataxin circuit controls keratinocyte differentiation by promoting the transcriptional termination of epidermal genes

Delta Np63, a master regulator of epithelial biology, is involved in regulating epithelial stem cell function, maintaining the integrity of stratified epithelial cells, and committing epidermal cells to the differentiation program. To this end, Delta Np63 exploits several direct mechanisms. Here, we elucidated a mechanism whereby Delta Np63 efficiently sustains the expression of epidermal differentiation genes. We show that Delta Np63 interacts with Senataxin (SETX), an RNA/DNA helicase able to resolve the R-loop intermediates over the GC-rich termination sites of coding genes. Notably, we found that SETX and ANp63 coregulate a subset of genes involved in the early step of the keratinocyte differentiation program. At the molecular level, SETX physically binds the p63 DNA-binding motifs present in two early epidermal differentiation genes, Keratin 1 (KRT1) and ZNF750, facilitating R-loop removal over their 3' ends and thus promoting efficient transcriptional termination and gene expression. Remarkably, SETX loss affects the activation of the proper epidermal differentiation program in vitro and impacts epidermal layer stratification in organotypic human skin. Furthermore, we found that SETX is mutated or downmodulated in squamous cell carcinoma (SCC), and SETX gene mutation is a negative prognostic factor for cutaneous SCC patient survival. Collectively, our results unveil SETX as a molecular player of skin homeostasis potentially involved in hyperproliferative skin disorders.