ZNF750 regulates skin barrier function independently of epidermal differentiation

Zinc finger protein 750 (Znf750) encodes an epithelial transcription factor with key roles in keratinocyte differentiation in vitro, and its autosomal dominant pathogenic mutations causes a psoriasis-like skin disease. However, the precise roles of Znf750 in skin development and epidermal barrier function in vivo are yet to be elucidated. Here, we utilize a Znf750 conditional knockout (cKO) mouse model to study Znf750 during epidermal development and skin barrier formation. Znf750 cKO mice demonstrated a delayed barrier function acquisition, substantial weight loss, and died shortly after birth. Remarkably and in contrast to previous in vitro studies, Znf750 cKO keratinocytes maintained epidermal differentiation program and formed a fully developed epidermis. In depth tissue analysis however, revealed ultrastructural defects in the granular and cornified layers of Znf750 cKO epidermis. At the molecular level, RNA-seq analysis demonstrated only mild alterations in the expression epidermal differentiation genes and epidermal barrier structural genes, but uncovered massive changes in immune-related pathways. Taken together, our studies demonstrated that while Znf750 is not essential for the epidermal differentiation process per se, it plays diverse roles in regulating skin barrier functions by controlling the expression of epidermal structural genes, as well as keratinocyte-mediated factors that crosstalk with the immune system. Further studies using our unique mouse model are expected to uncover molecular mechanisms by which the skin epidermis crosstalk with the immune system under normal conditions, and to provide new insights into pathways that goes awry in skin diseases with impaired barrier activity such as psoriasis.