Ma Zhangjing, Shi Huiyuan, Shen Yi, Li Huixia, Yang Yu, Yang Jiange, Zhao Hui, Wang Gang, Wang Jingqiang
1State Key Laboratory of Genetic Engineering and Collaborative Innovation Center of Genetics and Development, School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai, 200438 People's Republic of China.
Zhengzhou Revogene Inc, Zhengzhou, 450000 People's Republic of China.
Cell Biosci. 2019 Apr 11;9:34. doi: 10.1186/s13578-019-0296-9. eCollection 2019.
Previous studies have shown that in myogenic precursors, the homeoprotein Msx1 and its protein partners, histone methyltransferases and repressive histone marks, tend to be enriched on target myogenic regulatory genes at the nuclear periphery. The nuclear periphery localization of Msx1 and its protein partners is required for Msx1's function of preventing myogenic precursors from pre-maturation through repressing target myogenic regulatory genes. However, the mechanisms underlying the maintenance of Msx1 and its protein partners' nuclear periphery localization are unknown.
We show that an inner nuclear membrane protein, Emerin, performs as an anchor settled at the inner nuclear membrane to keep Msx1 and its protein partners Ezh2, H3K27me3 enriching at the nuclear periphery, and participates in inhibition of myogenesis mediated by Msx1. Msx1 interacts with Emerin both in C2C12 myoblasts and mouse developing limbs, which is the prerequisite for Emerin mediating the precise location of Msx1, Ezh2, and H3K27me3. The deficiency of Emerin in C2C12 myoblasts disturbs the nuclear periphery localization of Msx1, Ezh2, and H3K27me3, directly indicating Emerin functioning as an anchor. Furthermore, Emerin cooperates with Msx1 to repress target myogenic regulatory genes, and assists Msx1 with inhibition of myogenesis.
Emerin cooperates with Msx1 to inhibit myogenesis through maintaining the nuclear periphery localization of Msx1 and Msx1's protein partners.
先前的研究表明，在生肌前体细胞中，同源异型蛋白Msx1及其蛋白伴侣、组蛋白甲基转移酶和抑制性组蛋白标记，倾向于在核周的目标生肌调节基因上富集。Msx1及其蛋白伴侣在核周的定位是Msx1通过抑制目标生肌调节基因来防止生肌前体细胞过早成熟功能所必需的。然而，Msx1及其蛋白伴侣核周定位维持的潜在机制尚不清楚。
我们发现一种内核膜蛋白Emerin，作为一个锚定在内核膜上的蛋白，可使Msx1及其蛋白伴侣Ezh2、H3K27me3在核周富集，并参与Msx1介导的肌生成抑制。在C2C12成肌细胞和小鼠发育肢体中，Msx1均与Emerin相互作用，这是Emerin介导Msx1、Ezh2和H3K27me3精确定位的前提条件。C2C12成肌细胞中Emerin的缺失扰乱了Msx1、Ezh2和H3K27me3的核周定位，直接表明Emerin起到了锚定作用。此外，Emerin与Msx1协同抑制目标生肌调节基因，并协助Msx1抑制肌生成。
Emerin与Msx1协同作用，通过维持Msx1及其蛋白伴侣的核周定位来抑制肌生成。
