SUV39H1-dependent methyl-degron is a critical regulator of skeletal homeostasis.

Bone homeostasis and skeletal fragility are sexually dimorphic in humans, with postmenopausal women at the highest risk of osteoporosis. Here, we identify X-linked methyltransferase SUV39H1 as a suppressor of osteogenesis in females. Both experiments in primary samples and Suv39h1-deficient mice show enhanced osteogenesis upon SUV39H1 ablation with gender differences. Transcriptomic analysis reveals the aberrant NF-κB activation and inflammation signatures independent of H3K9me3 underlying SUV39H1-inhibited osteogenesis. Surprisingly, SUV39H1 shows a unique cytoplasmic distribution in female osteoblasts and is directly engaged in inflammation response by catalyzing IκBα methylation at lysine 38 adjacent to its degradation motif. This SUV39H1-deposited methylation mark signals UACA binding and subsequently restrains bone formation by provoking IκBα destabilization. Importantly, intrinsically improved osteogenesis by Suv39h1 depletion ameliorates ovariectomy-induced osteoporotic bone loss. Together with the chronologically elevated female SUV39H1 levels, these data identify an SUV39H1-governed molecular amplifier in sexually divergent skeletal remodeling and highlight its potential as therapeutic avenue for osteoporosis.