Keratinocyte Differentiation Transcription Factor ZNF750 Coordinates The Development Of Epidermal Immunocytes
2The National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev
Introduction: The epidermis, a critical protective barrier, comprises keratinocytes and immune cells that must develop in concert. While keratinocyte differentiation is well-regulated by transcription factors, the mechanisms governing concurrent epidermal immunocytes development remain elusive. This study investigates the role of ZNF750, a keratinocyte-specific transcription factor, in regulating both keratinocyte maturation and epidermal immunocytes development
Material and methods: We utilized neonatal mice with keratinocyte-specific conditional knockout of Znf750. Transcriptional analysis was performed on skin samples to identify changes in immune-related gene expression. Flow cytometry and immunohistochemistry were employed to examine the presence and maturation of epidermal-residing immune cells, with a focus on Langerhans cells.
Result and discussion: Transcriptional profiling revealed significant downregulation of immune-related genes in ZNF750-deficient keratinocytes. We observed a progressive depletion of 90% of the epidermal immunocytes, particularly Langerhans cells, while dermal immunocytes remained unaffected. Notably, remaining epidermal immunocytes lacked maturation markers, suggesting disrupted maintenance rather than differentiation. Mechanistically, we identified direct binding of ZNF750 to the IL-34 promoter, a key mediator of epidermal immunocytes survival and maintenance.
Conclusion: Our findings unveil ZNF750`s dual role in coordinating epidermal development by regulating keratinocyte differentiation and maintaining epidermal-residing immune cells through IL-34 expression. This study provides novel insights into the intricate regulation of epidermal immune cell development by keratinocytes, highlighting the complex interplay between structural and immune components in maintaining epidermal homeostasis. These findings may have implications for understanding and treating skin disorders characterized by disrupted barrier function and altered immune responses.