Histone methyltransferase Setd2 is critical for the proliferation and differentiation of myoblasts.
Histone methyltransferase Setd2 is critical for the proliferation and differentiation of myoblasts.
复制标题
组蛋白甲基转移酶 Setd2 对于成肌细胞的增殖和分化至关重要
DOI：
10.1016/j.bbamcr.2017.01.012
复制
发表时间：
2017-04
期刊：
影响因子：
--
通讯作者：
Chang J
中科院分区：
文献类型：
--
作者：
Yi X;Tao Y;Lin X;Dai Y;Yang T;Yue X;Jiang X;Li X;Jiang DS;Andrade KC;Chang J
骨骼肌细胞增殖和分化受到严格调控。表观遗传调控是这些过程的调控机制的主要组成部分。组蛋白修饰是用于染色质转录调节的表观遗传密码的一部分，通过以时间方式建立参与肌发生的基因的活性或抑制状态。在此，我们揭示了SET域包含2（Setd 2），一个重要的组蛋白3赖氨酸36三甲基转移酶，在调控成肌细胞的增殖和分化的功能。使用CRISPR/CAS9系统在骨骼肌成肌细胞系C2 C12中沉默Setd 2。突变细胞表现出肌管形成缺陷。肌管形成标志物，肌球蛋白重链（MHC），下调Setd 2沉默的细胞相比，野生型成肌细胞在分化过程中。Setd 2的缺陷也导致了肌细胞生成素（MyoG）表达的抑制，MyoG是分化过程中的关键肌细胞生成调节因子。除了成肌细胞分化缺陷之外，在Setd 2沉默细胞中观察到增殖速率降低，组蛋白3磷酸化水平显著降低，表明细胞增殖缺陷;这表明增殖表型受损。此外，受损的G1/S-和G2/M-相转变和细胞周期G1/S检查点，细胞周期蛋白D1，CDK 4，CDK 6和细胞周期蛋白E2的主要调节因子的表达水平降低检测在Setd 2沉默细胞。与细胞周期停滞表型一致，细胞周期蛋白依赖性激酶抑制剂p21在Setd 2沉默细胞中上调。总之，本研究证明了Setd 2在成肌细胞增殖和分化中的重要作用，并揭示了Setd 2通过调节MyoG和p21介导的分子机制。
Skeletal muscle cell proliferation and differentiation are tightly regulated. Epigenetic regulation is a major component of the regulatory mechanism governing these processes. Histone modification is part of the epigenetic code used for transcriptional regulation of chromatin through the establishment of an active or repressive state for genes involved in myogenesis in a temporal manner. Here, we uncovered the function of SET domain containing 2 (Setd2), an essential histone 3 lysine 36 trimethyltransferase, in regulating the proliferation and differentiation of myoblasts. Setd2 was silenced in the skeletal muscle myoblast cell line, C2C12, using the CRISPR/CAS9 system. The mutant cells exhibited defect in myotube formation. The myotube formation marker, myosin heavy chain (MHC), was downregulated earlier in Setd2 silenced cells compared to wild-type myoblasts during differentiation. The deficiency in Setd2 also resulted in repression of Myogenin (MyoG) expression, a key myogenic regulator during differentiation. In addition to the myoblast differentiation defect, decreased proliferation rate with significantly reduced levels of histone 3 phosphorylation, indicative of cell proliferation defect, were observed in the Setd2 silenced cells; suggesting an impaired proliferation phenotype. Furthermore, compromised G1/S- and G2/M-phase transition and decreased expression levels of major regulators of cell cycle G1/S checkpoints, cyclin D1, CDK4, CDK6, and cyclin E2 were detected in Setd2 silenced cells. Consistent with the cell cycle arrested phenotype, cyclin-dependent kinase inhibitor p21 was upregulated in Setd2 silenced cells. Together, this study demonstrates an essential role of Setd2 in myoblast proliferation and differentiation, and uncovers Setd2-mediated molecular mechanism through regulating MyoG and p21.
登录
查看更多内容
影响因子：
7.7
作者：
Carvalho S;Vítor AC;Sridhara SC;Martins FB;Raposo AC;Desterro JM;Ferreira J;de Almeida SF
通讯作者：
de Almeida SF
影响因子：
11.4
作者：
BRAUN, T;BUSCHHAUSENDENKER, G;ARNOLD, HH
通讯作者：
ARNOLD, HH
影响因子：
11.4
作者：
BRAUN, T;BOBER, E;ARNOLD, HH
通讯作者：
ARNOLD, HH
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
16.8
作者：
Aymard F;Bugler B;Schmidt CK;Guillou E;Caron P;Briois S;Iacovoni JS;Daburon V;Miller KM;Jackson SP;Legube G
通讯作者：
Legube G