Jmjd2C increases MyoD transcriptional activity through inhibiting G9a-dependent MyoD degradation

Abstract Skeletal muscle cell differentiation requires a family of proteins called myogenic regulatory factors(MRFs) to which MyoDbelongs. The activity of MyoDis under epigenetic regulation, however, the molecular mechanism by which histone KMTs and KDMs regulate MyoDtranscriptional activity through methylation remains to be determined. Here we provide evidence for a unique regulatory mechanism of MyoDtranscriptional activity through demethylationby Jmjd2C demethylasewhose level increases during muscle differentiation. G9a decreases MyoDstability via methylation-dependent MyoDubiquitination. Jmjd2C directly associates with MyoDin vitro and in vivo to demethylateand stabilize MyoD. The hypo-methylated MyoDdue to Jmjd2C is significantly more stable than hyper-methylated MyoDby G9a. Cul4/ Ddb1/Dcaf1 pathway is essential for the G9a-mediated MyoDdegradation in myoblasts. By the stabilization of MyoD, Jmjd2C increases myogenic conversion of mouse embryonic fibroblastsand MyoDtranscriptional activity with erasing repressive H3K9me3 level at the promoter of MyoDtarget genes. Collectively, Jmjd2C increases MyoDtranscriptional activity to facilitate skeletal muscle differentiation by increasing MyoDstability through inhibiting G9a-dependent MyoDdegradation.