Dnmt1 determines bone length by regulating energy metabolism of growth plate chondrocytes [RNA-seq]

Chondrocytes differentiated from mesenchymal stem cells play a role in determining skeletal patterns by ossification. However, it is still unclear how the maintenance DNA methylation in chondrocytes regulates differentiation and skeletal formation. In Musculoskeletal Knowledge Portal, Dnmt1 was significantly associated with “Height”. In fact, long bone of limb specific Dnmt1 deficient mice was significantly shortened due to decreased chondrocyte proliferation and accelerated differentiation. Furthermore, integrated analysis of RNA-Seq and MBD-Seq revealed that in Dnmt1ΔPrx1 chondrocytes, reduced DNA methylation resulted in an increase in energy metabolism-related genes in addition to ossification-related genes. Metabolomic analysis confirmed that almost all energy metabolites were increased in Dnmt1ΔPrx1 chondrocytes. These results indicate that Dnmt1 mediated maintenance DNA methylation governs chondrocyte differentiation by regulating energy metabolism through both gene expression and metabolite supply. Taken together, this study suggested that appropriate DNA methylation status in chondrocytes can orchestrate growth plate mineralization and subsequently determine bone length.