1305 Involucrin/ck1e/vitamin D receptor regulatory axis underlies evolution of human epidermis out of Africa

The human epidermis has evolved out of Africa. Increased involucrin (IVL) expression in the skin is associated with a near selective sweep Northern European populations compared to African. significance for this positive selection not clear. Our functional studies using Ivl-/- mice recently determined requirement positively regulate Vitamin D receptor and its activity epidermis. mouse treated MC903 (vitamin agonist) exhibited dampened Vdr response notable decreased expressions multiple scRNA-seq-identified keratinocyte populations. To further ascertain mechanism by which dosage impacts activity, we employed comprehensive multi-omics approach (ATAC-seq, RNA-seq, LC/MS proteomics) determine chromatin accessibility, transcriptomic, proteomic changes WT newborn (q<0.05). Csnk1e (casein kinase 1e) emerged as top candidate at intersect these differential datasets less accessible 3’UTR coinciding isoform reduced peptide protein (PK) domain observed skin. findings reveal an emerging genomic regulatory axis Ivl/Ck1e/Vdr keratinocytes. We next African ancestral epidermis, marked relatively lower IVL expression, decrease CK1e isoforms PK domains VDR higher expression. Together, our mouse-to-human translational identify conserved Ivl/CK1e/VDR that underlies evolution highlights population-specific, molecular diversity