Coordinated inhibition of SOX9 and cell-cycle progression by microRNA-200 restricts sebaceous gland fate specification

Abstract The microRNA-200 family (miR-200s) is known for inhibiting epithelial-to-mesenchymal transition and cell-cycle progression in cancer, but its function in epithelial development remains unclear. Here we show that miR-200s are highly enriched in hair matrix progenitors but absent from the upper hair follicle (HF), where sebaceous gland (SG) and HF stem cells are specified. Ectopic miR-200 induction abolishes SG specification while preserving hair morphogenesis. Genome-wide identification of miR-200 targets reveals direct repression of negative regulators of WNT signaling and cell-cycle regulators. Single-cell and spatial transcriptomic analyses uncover mutually exclusive domains of WNT activity and SOX9 expression in the upper HF that is disrupted by miR-200 induction. Genome-wide mapping of SOX9 targets further uncovers a lipogenic and fatty-acid metabolic program required for SG specification. Together, these findings show that miR-200 blocks SG fate by inhibiting SOX9 function and restricting cell proliferation, defining a spatially organized regulatory network essential for SG development.