EGR3 Is a Late Epidermal Differentiation Regulator that Establishes the Skin-Specific Gene Network

Lateepidermal differentiationis a key step of skin barrier formation; however, the specific genetic factors that distinguish late differentiationfrom early differentiationremain unknown. Here, we demonstrated that EGR3 is highly expressed in the stratum granulosum, and that it contributes to lateepidermal differentiation. However, its expression is lost under poorly differentiatedconditions, such as parakeratosis-lesional skin. EGR3 mediated the regulation of genes located in the epidermal differentiation complexthrough activation of enhancers and induction of enhancer RNAs. We further identified 20 targets of EGR3 specific for late differentiation. Additionally, we discovered that EGR3- and EGR3-related genes exhibited high tissue specificity on the skin. Through weighted gene co-expression analysis, EGR3 was found to be related to the keratinocyte differentiation-related module as an important part of the skin-specific genetic network. These findings shed light on the transcriptional regulation of lateepidermal differentiation, highlighting candidate targets for diseases related to disrupted differentiation.