Regulation of the dynamic chromatin architecture of the Epidermal Differentiation Complex is mediated by a c-Jun/AP-1-modulated enhancer

The Epidermal Differentiation Complex (EDC) locus comprises a syntenic and linear cluster of genes whose concomitant expression is a hallmark feature of differentiation in the developing skin epidermis. Many of the EDC proteins are cross-linked together to form the cornified envelope, an essential and discrete unit of the mammalian skin barrier. The mechanism underlying coordinate transcriptional activation of the EDC is unknown. Within the human EDC, we identified an epidermal-specific regulatory enhancer, 923, that responded to the developmental and spatio-temporal cues at the onset of epidermal differentiation in the mouse embryo. Comparative chromosomal conformation capture (3C) assays in proliferating and differentiated primary mouse keratinocytes revealed multiple chromatin interactions that were physiologically sensitive between the 923 enhancer and EDC gene promoters and thus depict the dynamic, chromatin topology of the EDC. We elucidate a mechanistic link between c-Jun/AP-1 and 923, whereby AP-1 and 923-mediated EDC chromatin remodeling is required for functional EDC gene activation. Thus, we identify a critical enhancer/transcription factor axis governing the dynamic regulation of the EDC chromatin architecture and gene expression and provide a framework for future studies towards understanding gene regulation in cutaneous diseases.