The transcription factor p63 is a key regulator in epithelial and epidermal development.Mutations in p63 give rise to rare epithelial related diseases with defects in skin,limb and orofacial development.We performed the first systematic and global analyses to identify p63-dependent target genes and a comprehensive atlas of gene regulatory networks during epidermal differentiation using a unique in vitro keratinocyte differentiation model.We show that skin disease genes with distinct phenotypes are expressed at different stages during epidermal differentiation,and many of them are likely regulated by p63.Surprisingly,we find that expression of p63-associated epidermal genes does not correlate with p63 binding,but rather with the active enhancer mark H3K27ac levels at the p63 binding sites,and not all p63 binding sites are active in epidermal cells.