BRN2 suppresses stress-induced hair greying

Abstract Adult stem cells maintain tissue homeostasis and regenerative capacity, but mechanisms preserving their integrity under stress remain incompletely understood. Here, we identify BRN2 (POU3F2), a POU-domain transcription factor, as a regulator of melanocyte lineage homeostasis and response to genotoxic stress. Single-cell transcriptomic analyses identified Brn2 among transcription factors preferentially active in melanocyte stem cells (McSCs), with BRN2 activity declining with age in human hair follicle melanocytic cells. Melanocyte-specific Brn2 deletion increased melanocyte differentiation and accumulation in the hair bulb, while downregulating DNA-repair and chromosome-maintenance programs. Despite these changes, Brn2 loss caused neither spontaneous hair greying nor detectable McSC depletion under steady-state conditions. Following ionizing radiation, however, Brn2 -deficient cells showed altered DNA-damage responses, reduced mitotic signatures, increased p53 and p21, and enhanced melanocytic differentiation. Irradiated Brn2 -deficient mice developed rapid, dose-dependent, permanent hair depigmentation associated with McSC and melanocyte depletion. Thus, BRN2 links POU-dependent transcriptional control to stem-cell resilience under genotoxic stress, preserving melanocyte regenerative capacity and protecting against irradiation-induced hair greying.