근육세포에서 G9a의존성 MyoD 분해를 억제하는 Jmjd2C에 의한 MyoD 전사조절에 대한 연구

Abstract

Skeletal muscle cells differentiation requires a family of proteins called myogenic regulatory factors (MRFs) to which MyoD belongs. The activity of MRFs is under epigenetic regulation, however, molecular mechanism by which histone KMTs and KDMs regulate MyoD transcriptional activity through methylation remains to be determined. Here we provide evidence for a unique regulatory mechanism of MyoD transcriptional activity through demethylation by Jmjd2C demethylase whose level increases during muscle differentiation. G9a decreases MyoD stability via methylation-dependent MyoD ubiquitination. Jmjd2C directly associates with MyoD in vitro and in vivo to demethylate MyoD that is methylated by G9a. The demethylated MyoD is significantly more stable than the G9a-methylated MyoD. Cul4/Ddb1/Dcaf1 pathway is essential for the G9a-methylated MyoD degradation in myoblasts, but not in myotubes. In addition to the stabilization of MyoD, Jmjd2C decreases repressive H3K9me3 level at the promoter of MyoD target genes. Collectively, Jmjd2C increases MyoD transcriptional activity to facilitate skeletal muscle differentiation by promoting MyoD stability and by decreasing repressive H3K9me3 level.