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 was significantly associated with “Height”. Long bones in the limbs of Dnmt1-deficient ( Dnmt1 ^ΔPrx1 ) mice are significantly shortened due to decreased chondrocyte proliferation and accelerated differentiation. Integrated analysis of RNA-Seq and MBD-Seq revealed that in Dnmt1 ^ΔPrx1 chondrocytes reduced DNA methylation resulted in increased expression of genes related to energy metabolism and to ossification. Metabolomic analyses confirmed that levels of nearly all energy metabolites were increased in Dnmt1 ^ΔPrx1 chondrocytes. These results indicate that Dnmt1-mediated maintenance 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.