Jmjd2C increases MyoD transcriptional activity through inhibiting G9a-dependent MyoD degradation
Jmjd2C increases MyoD transcriptional activity through inhibiting G9a-dependent MyoD degradation
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DOI：
10.1016/j.bbagrm.2015.07.001
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发表时间：
2015-08-01
影响因子：
4.7
通讯作者：
Kim, Kye-Seong
中科院分区：
文献类型：
--
作者：
Jung, Eun-Shil;Sim, Ye Ji;Kim, Kye-Seong
骨骼肌细胞分化需要MyoD所属的一组称为生肌调节因子(MRF)的蛋白质。MyoD的活性受到表观遗传的调节，然而，组蛋白KMTs和KDms通过甲基化调节MyoD转录活性的分子机制仍有待确定。在这里，我们提供了Jmjd2C去甲基化来调节MyoD转录活性的独特机制的证据，该去甲基酶的水平在肌肉分化过程中会增加。G9a通过甲基化依赖的MyoD泛素化降低MyoD的稳定性。Jmjd2C在体内外直接与MyoD结合，去甲基化和稳定MyoD。Jmjd2C的低甲基化MyoD比G9a高甲基化的MyoD更稳定。CUL4/DDB1/Daf1通路在G9a介导的成肌细胞MyoD降解中起着至关重要的作用。通过稳定MyoD，Jmjd2C通过消除MyoD靶基因启动子上的抑制H3K9me3水平，提高了小鼠胚胎成纤维细胞的肌源性转化和MyoD转录活性。总体而言，Jmjd2C通过抑制G9a依赖的MyoD降解来增加MyoD的稳定性，从而增加MyoD的转录活性，从而促进骨骼肌的分化。(C)2015爱思唯尔B.V.保留所有权利。
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. (C) 2015 Elsevier B.V. All rights reserved.