The methyl-CpG-binding protein CIBZ suppresses myogenic differentiation by directly inhibiting myogenin expression
The methyl-CpG-binding protein CIBZ suppresses myogenic differentiation by directly inhibiting myogenin expression
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DOI：
10.1038/cr.2011.90
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发表时间：
2011-11-01
期刊：
影响因子：
44.1
通讯作者：
Matsuda, Eishou
中科院分区：
文献类型：
--
作者：
Oikawa, Yu;Omori, Reiko;Matsuda, Eishou
骨骼肌的出生后生长和再生主要由卫星细胞进行，卫星细胞在刺激时开始表达肌细胞生成素（Myog），肌细胞生成分化的关键决定因素。DNA甲基化状态与Myog的表达有关，但其致病机制几乎仍不清楚。在这里，我们报告说，CIBZ，甲基-CpG结合蛋白的水平，减少卫星衍生的C2 C12细胞的肌源性分化，并在小鼠骨骼肌再生。我们目前的数据表明，CIBZ的损失促进肌分化，而外源性表达CIBZ损害它，在培养的细胞。CIBZ与Myog启动子近端区域结合，并以甲基化依赖性方式抑制Myog转录。这些数据表明CIBZ对肌源性分化的抑制至少部分依赖于Myog的调节。我们的数据表明，该近端Myog启动子的甲基化状态与Myog在细胞和组织中的转录呈负相关，并且在骨骼肌的出生后生长期间。值得注意的是，通过CIBZ抑制诱导Myog转录不依赖于Myog启动子中CpG位点的去甲基化。这些观察结果提供了第一个报告的分子机制，说明Myog转录是如何协调调节的甲基-CpG结合蛋白和甲基化状态的近端Myog启动子。
Postnatal growth and regeneration of skeletal muscle are carried out mainly by satellite cells, which, upon stimulation, begin to express myogenin (Myog), the critical determinant of myogenic differentiation. DNA methylation status has been associated with the expression of Myog, but the causative mechanism remains almost unknown. Here, we report that the level of CIBZ, a methyl-CpG-binding protein, decreases upon myogenic differentiation of satellite-derived C2C12 cells, and during skeletal muscle regeneration in mice. We present data showing that the loss of CIBZ promotes myogenic differentiation, whereas exogenous expression of CIBZ impairs it, in cultured cells. CIBZ binds to a Myog promoter-proximal region and inhibits Myog transcription in a methylation-dependent manner. These data suggest that the suppression of myogenic differentiation by CIBZ is dependent, at least in part, on the regulation of Myog. Our data show that the methylation status of this proximal Myog promoter inversely correlates with Myog transcription in cells and tissues, and during postnatal growth of skeletal muscle. Notably, induction of Myog transcription by CIBZ suppression is independent of the demethylation of CpG sites in the Myog promoter. These observations provide the first reported molecular mechanism illustrating how Myog transcription is coordinately regulated by a methyl-CpG-binding protein and the methylation status of the proximal Myog promoter.