CASZ1 and ZNF750 act redundantly to preserve differentiation programs in the developing mouse epidermis

Summary: The epidermis is a constantly renewing stratified epithelial tissue that provides essential protective barrier functions. Disruptions to epidermal differentiation characterize various skin disorders. In search for regulators of epidermal differentiation, we have recently identified Castor zinc finger 1 (CASZ1) as a new transcription factor (TF) essential for <i>in vitro</i> keratinocyte differentiation program. Interestingly however, the epidermal deletion of murine <i>Casz1 </i>did not impair gross epidermal development and stratification, suggesting that<i> in vivo</i> loss of CASZ1 may be compensated for by other TF(s). Here, we uncover that such compensatory mechanism exists between CASZ1 and ZNF750 – a key driver of keratinocyte differentiation programs. We show that CASZ1-dependent genes are most significantly enriched for the co-binding of ZNF750 in epidermal keratinocytes. Importantly, we demonstrate that the co-ablation of both TFs in the developing mouse epidermis markedly aggravates the phenotypes of single knockout (KO) mice, impairs the induction of terminal differentiation genes such as filaggrin and loricrin otherwise expressed in single KOs, and leads to compromised inward and outward barrier functions, resulting in early postnatal lethality. Together, our studies highlight <i>in vivo</i> compensatory feedback mechanisms, in which two epidermal TFs can act redundantly to provide a regulatory safety net preserving epidermal development programs and the establishment of essential barrier functions. Liat Oss-Ronen¹, Topaz Alfer¹, Hilla Levi¹, Idan Cohen¹ 1. Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Be'er Sheva, South District, Israel. Epidermal Structure and Barrier Function