H2AK119ub dynamics control hair follicle stem cell quiescence

Adult stem cells (SCs) transition between quiescent and active states to maintain tissue integrity, and dysregulation of this balance can lead to tissue degeneration, cancer, or premature aging. Both intrinsic factors and extrinsic niche signals influence these states; however, the molecular mechanisms that integrate extrinsic cues with intrinsic programs remain poorly understood. Here, we show that the conserved repressive histone mark, H2AK119ub, serves as a molecular switch linking inhibitory fibroblast growth factor (FGF) signals with the quiescent transcriptional program in hair follicle stem cells (HFSCs). Modulation of FGF signaling is associated with changes in H2AK119ub levels, thereby toggling HFSCs between quiescence and activation states. Mechanistically, H2AK119ub directly represses a proliferation-promoting transcriptional program preserving HFSC quiescence. Loss of H2AK119ub in HFSCs shortens the quiescent phase and induces repeated rounds of HFSC activation, ultimately leading to SC exhaustion – a hallmark of aging tissue. Analysis of other mammalian SC systems and Drosophila germline SCs confirms that H2AK119ub is a broadly conserved hallmark of quiescence and is dynamic upon SC activation. These findings reveal a signaling-epigenetic axis that controls SC quiescence and underscores the importance of the conserved role of H2AK119ub in maintaining tissue homeostasis.