Zhang Haoyuan, Wang Sheng, Zhou Qiangwei, Liao Yinlong, Luo Wenzhe, Peng Zhelun, Ren Ruimin, Wang Heng
Key Laboratory of Agricultural Animal Genetics, Breeding and Reproduction of the Ministry of Education, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, China.
Agricultural Bioinformatics Key Laboratory of Hubei Province, Hubei Engineering Technology Research Center of Agricultural Big Data, 3D Genomics Research Center, College of Informatics, Huazhong Agricultural University, Wuhan, China.
Cell Death Discov. 2022 Apr 30;8(1):236. doi: 10.1038/s41420-022-01041-1.
Skeletal muscle myogenesis is a sophisticated process controlled by genetic and epigenetic regulators. In animals, one of the key enzymes for the DNA demethylation of 5-methylcytosine is TET2. Although TET2 is essential for muscle development, the mechanisms by which TET2 regulates myogenesis, particularly the implication for muscle stem cells, remains unclear. In the present study, we employed the TET2 knockout mouse model to investigate the function of TET2 in muscle development and regeneration. We observed that TET2 deficiency caused impaired muscle stem cell proliferation and differentiation, resulting in the reduction in both myofiber number and muscle tissue size. Specifically, TET2 maintains calcium homeostasis in muscle stem cells by controlling the DNA methylation levels of the calcium pathway genes. Forced expression of the sodium/calcium exchanger protein SLC8A3 could rescue the myogenic defects in TET2 knockout cells. Our data not only illustrated the vital function of TET2 during myogenesis but also identified novel targets that contribute to calcium homeostasis for enhancing muscle function.
骨骼肌生成是一个由遗传和表观遗传调节因子控制的复杂过程。在动物中，5-甲基胞嘧啶DNA去甲基化的关键酶之一是TET2。尽管TET2对肌肉发育至关重要，但其调节肌生成的机制，尤其是对肌肉干细胞的影响仍不清楚。在本研究中，我们采用TET2基因敲除小鼠模型来研究TET2在肌肉发育和再生中的功能。我们观察到，TET2缺陷导致肌肉干细胞增殖和分化受损，从而导致肌纤维数量和肌肉组织大小减少。具体而言，TET2通过控制钙通路基因的DNA甲基化水平来维持肌肉干细胞中的钙稳态。强制表达钠/钙交换蛋白SLC8A3可以挽救TET2基因敲除细胞中的成肌缺陷。我们的数据不仅阐明了TET2在肌生成过程中的重要功能，还确定了有助于钙稳态以增强肌肉功能的新靶点。
