Muscle regeneration controlled by a designated DNA dioxygenase.
Muscle regeneration controlled by a designated DNA dioxygenase.
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由指定 DNA 双加氧酶控制的肌肉再生
DOI：
10.1038/s41419-021-03817-2
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发表时间：
2021-05-25
影响因子：
9
通讯作者：
Hu P
中科院分区：
文献类型：
--
作者：
Wang H;Huang Y;Yu M;Yu Y;Li S;Wang H;Sun H;Li B;Xu G;Hu P
Tet双加氧酶负责活跃的DNA去甲基化。Tet蛋白在肌肉再生中的作用尚未得到很好的研究。在这里，我们发现TET2，而不是Tet1和Tet3，是体内肌肉再生所特需的。TET2的缺失会导致严重的肌肉再生缺陷。进一步分析表明，TET2调控成肌细胞的分化和融合。TET2通过主动去甲基化肌细胞生成素(MyoG)的增强子区域来激活其转录。MyoGin TET2 KO成肌细胞的重新表达挽救了分化和融合缺陷。进一步的机制分析表明，TET2通过去甲基化E盒侧翼的CpG位点来增强MyoD结合，促进活性组蛋白修饰的招募，增加染色质的可及性并激活其转录。这些发现为DNA甲基化和先驱转录因子活性调控提供了新的线索。
Tet dioxygenases are responsible for the active DNA demethylation. The functions of Tet proteins in muscle regeneration have not been well characterized. Here we find that Tet2, but not Tet1 and Tet3, is specifically required for muscle regeneration in vivo. Loss of Tet2 leads to severe muscle regeneration defects. Further analysis indicates that Tet2 regulates myoblast differentiation and fusion. Tet2 activates transcription of the key differentiation modulatorMyogenin(MyoG) by actively demethylating its enhancer region. Re-expressing ofMyoGin Tet2 KO myoblasts rescues the differentiation and fusion defects. Further mechanistic analysis reveals that Tet2 enhances MyoD binding by demethylating the flanking CpG sites of E boxes to facilitate the recruitment of active histone modifications and increase chromatin accessibility and activate its transcription. These findings shed new lights on DNA methylation and pioneer transcription factor activity regulation.
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