Keratinocyte differentiation transcription factor ZNF750 coordinates the development of epidermal immunocytes

The epidermis consists of keratinocytes and immunocytes that co-develop to form protective physical and immunological barriers. The differentiation of cells is regulated by transcription factors; however, regulation of coordinated development of several cell types within a tissue remains a mystery. Here, we show that ZNF750, a keratinocyte maturation factor, is essential for epidermal immunocytes at late fetal development. Transcriptional analysis of neonatal mice lacking Znf750 in keratinocytes revealed downregulation of immune-signature genes. In accord, we uncovered that embryonic loss of ZNF750 causes a progressive deficiency of epidermis-resident immunocytes, primarily of the Langerhans cell (LC) lineage, while dermal immunocytes remain intact. Residual epidermal LCs do not lack maturation markers. Mechanistically, ZNF750 binds upstream to the promoter of IL34, an LCs maintenance factor, and induces its expression. Together, our study finds that ZNF750 coordinates tissue development, demonstrating how a single transcription factor of keratinocytes also regulates the development of immunocytes in the epidermis.