ZNF750 Regulates Skin Barrier Function by Driving Cornified Envelope and Lipid Processing Pathways

The epidermis is a constantly renewing stratified epithelial tissue that provides essential protective barrier functions. The major barrier is located at the outermost layers of the epidermis, formed by terminally differentiated keratinocytes reinforced by proteins of their cornified envelope and sequestered intercellular lipids. Disruptions to epidermal differentiation characterize various skin disorders. ZNF750 is an epithelial transcription factor essential for in vitro keratinocyte differentiation, whose truncating mutation in humans causes autosomal dominant psoriasis-like skin disease. In this study, we utilized an epidermal-specific Znf750 conditional knockout mouse model to uncover the role ZNF750 plays in epidermal development. We show that deletion of Znf750 in the developing skin does not block epidermal differentiation completely, suggesting in vivo compensatory feedback mechanisms, although it does result in impaired barrier function and perinatal lethality. Molecular dissection revealed ultrastructural defects in the differentiated layers of the epidermis, accompanied by alterations in the expression of ZNF750-dependent genes encoding key cornified envelope precursor proteins and lipid-processing enzymes, including gene subsets known to be mutated in human skin diseases involving impaired barrier function. Together, our findings provide molecular insights into the pathogenesis of human skin disease by linking ZNF750 to a subset of epidermal differentiation genes involved in barrier formation pathways.