Dnmt1 determines bone length by regulating energy metabolism of growth plate chondrocytes

Chondrocytes differentiated from mesenchymal stem cells play a role in determining skeletal patterns by ossification. However, the mechanism by which maintenance DNA methylation in chondrocytes regulates differentiation and skeletal formation is unclear. In the Musculoskeletal Knowledge Portal, Dnmt1 is significantly associated with Height. Long bones in Dnmt1-deficient (Dnmt1^ΔPrx1) mouse limbs are significantly shortened due to decreased chondrocyte proliferation and accelerated differentiation. Integrated analysis of RNA-Seq and MBD-Seq reveals that reduced DNA methylation in Dnmt1^ΔPrx1 chondrocytes leads to increased expression of genes related to energy metabolism and to ossification. Metabolomic analyses confirm that Dnmt1^ΔPrx1 chondrocytes had increased levels of nearly all energy metabolites. These results indicate that Dnmt1-mediated maintenance of DNA methylation governs chondrocyte differentiation by regulating energy metabolism through both gene expression and modulation of metabolite supplies. Taken together, this study suggests that appropriate DNA methylation status in chondrocytes can orchestrate growth plate mineralization and subsequently determine bone length.