Sodium arsenite represses the expression of myogenin in C2C12 mouse myoblast cells through histone modifications and altered expression of Ezh2, Glp, and Igf-1.
Sodium arsenite represses the expression of myogenin in C2C12 mouse myoblast cells through histone modifications and altered expression of Ezh2, Glp, and Igf-1.
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DOI：
10.1016/j.taap.2012.03.002
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发表时间：
2012-05-01
影响因子：
3.8
通讯作者：
Bain, Lisa J.
中科院分区：
文献类型：
--
作者：
Hong, Gia-Ming;Bain, Lisa J.
砷是一种常见于水系统中的有毒物质，长期接触会导致不良发育影响，包括新生儿死亡、死产和流产增加、出生体重低和运动活动改变。先前的研究表明，20 nM亚砷酸钠暴露于C2 C12小鼠肌细胞延迟成肌细胞分化，由于肌细胞生成素表达减少，肌细胞生成素是将成肌细胞分化为肌管的转录因子。在这项研究中，砷可以改变肌细胞生成素表达的几种机制进行了研究。将分化中的C2 C12细胞暴露于20 nM砷使H3 K9二甲基化（H3 K9 me 2）和H3 K9三甲基化（H3 K9 me 3）在肌细胞生成素的转录起始位点附近增加了3倍，这表明抑制标记增加，并且使H3 K9乙酰化（H3 K9 Ac）减少了0.5倍，这表明允许标记减少。在砷暴露的细胞中，Glp或H3-K9甲基转移酶Ehmt 1的蛋白表达也增加了1.6倍。除了改变组蛋白重塑状态的肌细胞生成素启动子，蛋白质和mRNA水平的Igf-1，肌生长因子，显着抑制砷暴露。此外，在砷处理的细胞中检测到Ezh 2表达的2倍诱导，以及Ezh 2（3.3倍）和Dnmt 3a（~2倍）在转录起始位点（-40至+42）处向肌细胞生成素启动子的募集增加。总之，我们得出结论，砷暴露的C2 C12细胞中抑制的肌生成素表达可能是由于Igf-1表达减少、Ezh 2的核表达增强和启动子募集以及肌生成素启动子上组蛋白重塑状态改变（−40至+42）的组合。
Arsenic is a toxicant commonly found in water systems and chronic exposure can result in adverse developmental effects including increased neonatal death, stillbirths, and miscarriages, low birth weight, and altered locomotor activity. Previous studies indicate that 20 nM sodium arsenite exposure to C2C12 mouse myocyte cells delayed myoblast differentiation due to reduced myogenin expression, the transcription factor that differentiates myoblasts into myotubes. In this study, several mechanisms by which arsenic could alter myogenin expression were examined. Exposing differentiating C2C12 cells to 20 nM arsenic increased H3K9 dimethylation (H3K9me2) and H3K9 trimethylation (H3K9me3) by 3-fold near the transcription start site of myogenin, which is indicative of increased repressive marks, and reduced H3K9 acetylation (H3K9Ac) by 0.5-fold, indicative of reduced permissive marks. Protein expression of Glp or Ehmt1, a H3-K9 methyltransferase, was also increased by 1.6-fold in arsenic–exposed cells. In addition to the altered histone remodeling status on the myogenin promoter, protein and mRNA levels of Igf-1, a myogenic growth factor, were significantly repressed by arsenic exposure. Moreover, a 2-fold induction of Ezh2 expression, and an increased recruitment of Ezh2 (3.3-fold) and Dnmt3a (~2-fold) to the myogenin promoter at the transcription start site (−40 to +42), were detected in the arsenic-treated cells. Together, we conclude that the repressed myogenin expression in arsenic-exposed C2C12 cells was likely due to a combination of reduced expression of Igf-1, enhanced nuclear expression and promoter recruitment of Ezh2, and altered histone remodeling status on myogenin promoter (−40 to +42).
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