Single Cell and Open Chromatin Analysis Reveals Molecular Origin of Epidermal Cells of the Skin

How embryonic progenitors coordinate cell fate specification and establish transcriptional and signaling competence is a fundamental question in developmental biology. Here, we show that transcription factor Delta Np63 profoundly changes the transcriptome and remodels thousands of open chromatin regions of Krt8+ progenitors during epidermal fate specification. ATAC-seq and single-cell RNA-seq reveal that Delta Np63-dependent programs govern epidermal lineage formation, and Delta Np63-independent programs, mediated by AP2 and AP1 transcription factors, promote epidermal differentiation and epithelial-to-mesenchymal transition. Delta Np63 promotes Wnt signaling by directly upregulating Wnt ligands, Frizzled receptors, and transcription factors. Deletion of beta-catenin in Krt8+ progenitors delays their maturation into Krt5+ progenitors. The lack of epidermal Wnt production in the absence of Delta Np63 also incapacitates Wnt activation in the underlying dermal cells. These findings reveal the remarkable changes of the transcriptome, open chromatin, and signaling pathways at the onset of skin development and uncover the molecular cascade for epidermal lineage formation.