223 Skin barrier, inflammation, and metabolism– connections through Ovol1/Ovol2

Abstract

Skin barrier dysfunction contributes to inflammatory diseases such as psoriasis and atopic dermatitis, which can lead to systemic defects (e.g. atopic march). The cellular and molecular events that regulate barrier-induced inflammation and its connection to whole-body physiology remain to be fully understood. SNPs in human OVOL1, which encodes a transcriptional repressor, are associated with many skin inflammatory diseases. Germline deletion of Ovol1 leads to epidermal hyperproliferation and a transient delay in embryonic skin barrier acquisition. However, the function of Ovol1 and its homolog Ovol2 in adult skin homeostasis and inflammation is unknown. Here we show that skin epithelia-specific deletion of Ovol1 results in radically aggravated barrier disruption and psoriasis-like inflammation upon stimulation with imiquimod. Using ChIP-seq we found that Ovol1 protein in epidermal cells directly binds to the promoters of not only genes involved in controlling proliferation and differentiation (e.g. Id1) but also genes involved in inflammation (e.g. Cxcl1 and Nfkb2). We generated mice with both Ovol1 and Ovol2 inducibly deleted in adulthood specifically in epidermal cells and found the mice to rapidly develop skin barrier defects. Subsequently, they developed oversized paws with elongated and reddish toenails, and lower bodyweight and reduced fat deposits. Preliminary analysis using metabolic cages shows that these mice eat more and are metabolically more active than their control littermates. Additionally, they release more heat while maintaining a normal body temperature. Current experiments focus on characterizing potential inflammation in mutant mice and analyzing gene expression changes in skin and metabolic tissues such as brown adipose tissue of these mice. Our goal is to elucidate the mechanism by which Ovol1 and Ovol2 regulate skin barrier function and inflammation, and how cutaneous defects are linked to alterations in whole-body physiology and metabolism.