Epigenetic Regulation of Myofibroblast Differentiation by DNA Methylation
Epigenetic Regulation of Myofibroblast Differentiation by DNA Methylation
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DOI：
10.2353/ajpath.2010.090999
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发表时间：
2010-07-01
影响因子：
6
通讯作者：
Phan, Sem H.
中科院分区：
文献类型：
--
作者：
Hu, Biao;Gharaee-Kermani, Mehrnaz;Phan, Sem H.
DNA甲基化是抑制基因表达的关键机制，在控制发育和细胞分化方面具有特殊的相关性。我们分析了a-平滑肌肌动蛋白（α - sma）基因DNA甲基化的程度和调控，以阐明其在肌成纤维细胞分化中的潜在作用。这些实验揭示了在成纤维细胞、肌成纤维细胞和肺泡上皮型H细胞中存在三个不同水平甲基化的CpG岛。协调地，这些细胞分别表达低、高或无a-SMA。此外，使用特异性小干扰RNA抑制DNA甲基转移酶活性或敲低DNA甲基转移酶可在成纤维细胞中显著诱导a-SMA。相反，诱导DNA甲基转移酶过表达抑制了a-SMA基因的表达。转化生长因子13诱导的肌成纤维细胞分化分别通过下调或过表达DNA甲基转移酶而增强或抑制。最后，a-SMA启动子的体外DNA甲基化抑制了其活性。这些结果提示，DNA甲基化酶介导的DNA甲基化是肌成纤维细胞分化过程中a-SMA基因表达调控的重要机制。（中国病理杂志2010,177.21-28;DOI: 10.2353/ajpath.2010.090999）
DNA methylation, a key mechanism of repressing gene expression, is of particular relevance in controlling development and cell differentiation. We analyzed the extent and regulation of DNA methylation of the a-smooth muscle actin (alpha-SMA) gene to elucidate its potential role in myofibroblast differentiation. These experiments revealed the presence of three CpG islands that were methylated at different levels in fibroblasts, myofibroblasts, and alveolar epithelial type H cells. Coordinately, these cells expressed low, high, or no a-SMA, respectively. In addition, inhibition of DNA methyltransferase activity or knock down of DNA methyltransferase using specific small interfering RNA caused significant induction of a-SMA in fibroblasts. In contrast, induced overexpression of DNA methyltransferase suppressed a-SMA gene expression. Transforming growth factor 13 induced myofibroblast differentiation was enhanced or suppressed by knockdown or overexpression of DNA methyltransferase, respectively. Finally, in vitro DNA methylation of the a-SMA promoter suppressed its activity. These findings suggest that DNA methylation mediated by DNA methyltransferase is an important mechanism regulating the a-SMA gene expression during myofibroblast differentiation. (Am J Pathol 2010, 177.21-28; DOI: 10.2353/ajpath.2010.090999)