title: 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 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.
authors.affiliation: Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Eun-Shil
authors.initials: ES
authors.lastname: Jung
authors.affiliation: Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Ye-Ji
authors.initials: YJ
authors.lastname: Sim
authors.affiliation: Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Hoe-Su
authors.initials: HS
authors.lastname: Jeong
authors.affiliation: Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 133-791, Republic of Korea.
authors.forename: Ye-Jin
authors.initials: YJ
authors.lastname: Yun
authors.affiliation: Bio Focus Co., Ltd., Gyeonggi-do 437-753, Republic of Korea.
authors.forename: Joo-Hoon
authors.initials: JH
authors.lastname: Song
authors.affiliation: Department of Biological & Environmental Science, Dongguk University, Seoul 100-175, Republic of Korea.
authors.forename: Su-Hee
authors.initials: SH
authors.lastname: Jeon
authors.affiliation: Samsung Biomedical Research Institute, School of Medicine, Sungkyunkwan University, Seoul 135-710, Republic of Korea.
authors.forename: Chungyoul
authors.initials: C
authors.lastname: Choe
authors.affiliation: Center for Cancer Research, Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Kyung-Tae
authors.initials: KT
authors.lastname: Park
authors.affiliation: Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 133-791, Republic of Korea. Electronic address: chakimster@gmail.com.
authors.forename: Chang-Hoon
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul 133-791, Republic of Korea. Electronic address: ks66kim@hanyang.ac.kr.
authors.forename: Kye-Seong
authors.initials: KS
authors.lastname: Kim
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation; D044127:Epigenesis, Genetic / Q000502:physiology; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases; D051379:Mice; D024510:Muscle Development / Q000235:genetics; D018482:Muscle, Skeletal / Q000502:physiology; D017570:MyoD Protein / Q000378:metabolism* / Q000502:physiology; D032446:Myoblasts / Q000502:physiology; D010089:Oxidoreductases, N-Demethylating / Q000502:physiology*; D059748:Proteolysis; D015533:Transcriptional Activation
chemical_list: D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C544194:Jmjd2c protein, mouse; D056484:Jumonji Domain-Containing Histone Demethylases; D010089:Oxidoreductases, N-Demethylating; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase
keywords: G9a; Jmjd2C; Methylation-dependent MyoD degradation; Skeletal muscle differentiation