Increasing evidence suggests that microRNAs may play important roles in regulating self-renewal and differentiation in mammalian stem cells (SCs). Here, we explore this issue in skin. We first characterize microRNA expression profiles of skin SCs versus their committed proliferative progenies and identify a microRNA subset associating with "stemness." Of these, miR-125b is dramatically downregulated in early SC progeny. We engineer an inducible mice system and show that when miR-125b is sustained in SC progenies, tissue balance is reversibly skewed toward stemness at the expense of epidermal, oil-gland, and HF differentiation. Using gain- and loss-of-function in vitro, we further implicate miR-125b as a repressor of SC differentiation. In vivo, transcripts repressed upon miR-125b induction are enriched >700% for predicted miR-125b targets normally downregulated upon SC-lineage commitment. We verify some of these miR-125b targets, and show that Blimp1 and VDR in particular can account for many tissue imbalances we see when miR-125b is deregulated.
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