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

• Published in: Biochimica et biophysica acta Vol. 1849; no. 8; pp. 1081 - 1094
• Main Authors: Jung, Eun-Shil, Sim, Ye-Ji, Jeong, Hoe-Su, Kim, Su-Jin, Yun, Ye-Jin, Song, Joo-Hoon, Jeon, Su-Hee, Choe, Chungyoul, Park, Kyung-Tae, Kim, Chang-Hoon, Kim, Kye-Seong
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-08-2015
• Subjects: Animals; Cell Differentiation - genetics; Cells, Cultured; Down-Regulation; Epigenesis, Genetic - physiology; G9a; HEK293 Cells; Histone-Lysine N-Methyltransferase - metabolism; Humans; Jmjd2C; Jumonji Domain-Containing Histone Demethylases; Methylation-dependent MyoD degradation; Mice; Muscle Development - genetics; Muscle, Skeletal - physiology; Myoblasts - physiology; MyoD Protein - metabolism; MyoD Protein - physiology; Oxidoreductases, N-Demethylating - physiology; Proteolysis; Skeletal muscle differentiation; Transcriptional Activation; Skeletal muscle differentiation; Jmjd2C; Methylation-dependent MyoD degradation; G9a
• ISSN: 1874-9399; 0006-3002; 1876-4320
• DOI: 10.1016/j.bbagrm.2015.07.001

Skeletal muscle cell differentiation requires a family of proteins called myogenic regulatory factors (MRFs) to which MyoD belongs. The activity of MyoD is under epigenetic regulation, however, the 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 and stabilize MyoD. The hypo-methylated MyoD due to Jmjd2C is significantly more stable than hyper-methylated MyoD by G9a. Cul4/Ddb1/Dcaf1 pathway is essential for the G9a-mediated MyoD degradation in myoblasts. By the stabilization of MyoD, Jmjd2C increases myogenic conversion of mouse embryonic fibroblasts and MyoD transcriptional activity with erasing repressive H3K9me3 level at the promoter of MyoD target genes. Collectively, Jmjd2C increases MyoD transcriptional activity to facilitate skeletal muscle differentiation by increasing MyoD stability through inhibiting G9a-dependent MyoD degradation.
•G9a induces methylation-dependent MyoD degradation.•Dcaf1 acts as E3 ligase for G9a-methylated MyoD.•Jmjd2C demethylates G9a-methylated MyoD.•Hypo-methylated MyoD by Jmjd2C is more stable than methylated MyoD.•Jmjd2C increases MyoD transcriptional activity by increasing MyoD stability.