Essential Role of MeCP2 in the Regulation of Myofibroblast Differentiation during Pulmonary Fibrosis
Essential Role of MeCP2 in the Regulation of Myofibroblast Differentiation during Pulmonary Fibrosis
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DOI：
10.1016/j.ajpath.2011.01.002
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发表时间：
2011-04-01
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甲基化是抑制成纤维细胞基因表达的关键机制，包括α-平滑肌肌动蛋白(α-SMA)基因的表达。然而，与甲基化的α-SMA基因相互作用以调节其表达的反式作用因子尚未确定。通过凝胶漂移和染色质免疫沉淀(ChIP)实验，证明甲基CpG结合蛋白2(MeCP2)可与α-SMA基因结合。在MeCP2基因敲除小鼠分离的肺成纤维细胞中，siRNA或其缺陷抑制了MeCP2基因的表达，导致α-SMA基因的表达显著降低。相反，瞬时将MeCP2表达载体导入成纤维细胞可增强α-SMA基因的表达。此外，体内研究表明，与野生型小鼠相比，气管内注射博莱霉素后，MeCP2缺陷小鼠的肺泡壁厚度、炎症细胞浸润、间质胶原沉积和肌纤维母细胞分化显著减少。因此，MeCP2在肌成纤维细胞分化和肺纤维化中起着至关重要的作用。(Am J Pathol2011,1781500-1508；DOI：10.1016/j.ajpath.2011.01.002)
DNA methylation is a key mechanism for repression of gene expression, including that of alpha-smooth muscle actin (alpha-SMA) gene expression in fibroblasts. However, the trans-acting factors that interact with the methylated alpha-SMA gene to regulate its expression have not been identified. Using gel shift and chromatin immunoprecipitation (ChIP) assays, methyl CpG binding protein 2 (MeCP2) was shown to bind to the alpha-SMA gene. Suppression of MeCP2 gene expression by siRNA or its deficiency in lung fibroblasts isolated from MeCP2 knockout mice caused significant reduction of alpha-SMA gene expression. In contrast, transient transfection of MeCP2 expression plasmid into fibroblasts enhanced alpha-SMA gene expression. Moreover, in vivo studies revealed that compared to their wild type littermates, MeCP2-deficient mice exhibited significantly decreased alveolar wall thickness, inflammatory cell infiltration, interstitial collagen deposition, and myofibroblast differentiation in response to endotracheal injection of bleomycin. Thus, MeCP2 is essential for myofibroblast differentiation and pulmonary fibrosis. (Am J Pathol 2011, 178:1500-1508; DOI: 10.1016/j.ajpath.2011.01.002)