KDM6B safeguards mineralized tissue homeostasis from mechanical stress through epigenetic control of PIEZO1-mediated mechanotransduction in the mouse incisor.

Mechanical forces shape the growth and regeneration of mineralized tissues such as bones and teeth, yet how these tissues adapt to sustained mechanical stress remains poorly understood. Here, using mouse incisor models with varying degrees of loading, we identified that the histone demethylase KDM6B is a critical epigenetic regulator that preserves mineralized tissue homeostasis by protecting progenitor transit-amplifying cells from mechanical stress-induced apoptosis. Loss of Kdm6b impairs this balance by enhancing PIEZO1-dependent mechanotransduction, leading to excessive Ca2+ influx and apoptosis in transit-amplifying cells. Mechanistically, Kdm6b deficiency increases H3K27me3 at the Bmi1 promoter, silencing its expression and derepressing Piezo1 expression. Importantly, Piezo1 haploinsufficiency in Kdm6b-deficient mice restores Ca2+ influx restriction, rescuing transit-amplifying cell defects and tissue homeostasis. These findings reveal that KDM6B-H3K27me3-BMI1-PIEZO1 is a critical epigenetic "mechanostat" that protects dental progenitor cells from mechanical stress, ensuring sustained tissue homeostasis. This chromatin-based mechanism of tissue mechano-adaptation could be targeted to prevent mechanically induced degeneration in mineralized tissues.