Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts
Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts
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DOI：
10.1002/art.21948
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发表时间：
2006-07-01
影响因子：
--
通讯作者：
Kahaleh, Bashar
中科院分区：
文献类型：
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作者：
Wang, Youngqing;Fan, Pan-Sheng;Kahaleh, Bashar
目标。硬皮病是一种以血管病变和广泛的器官纤维化为特征的自身免疫性疾病。无论是在体内还是体外，成纤维细胞功能的改变都被很好地记录下来，并通过细胞外基质蛋白的合成和沉积增加来说明。我们开展了这项研究，以探讨表观遗传机制在改变的SSC成纤维细胞表型的出现和持续存在中的可能性。检测DNA甲基转移酶和组蛋白脱乙酰酶抑制剂对成纤维细胞胶原表达和表观遗传介质水平的影响。检测瞬时转导FLI1基因的SSC成纤维细胞和转导反义FLI1基因的正常细胞对胶原蛋白表达的影响。检测培养细胞、SSC和正常皮肤活检标本中FLI1启动子的甲基化状态。SSC成纤维细胞中的表观遗传介质水平增加。在细胞培养中加入表观遗传抑制物可使SSC成纤维细胞中的胶原表达正常化。SSC成纤维细胞的胶原合成增加与胶原抑制基因FLI1的表观遗传抑制有关。在SSC成纤维细胞和皮肤活检标本中，FI1启动子区域的CpG岛高度甲基化。本研究结果提示，表观遗传机制可能介导了SSC的纤维化表现。导致SSC纤维化表型的信号转导似乎集中在DNA甲基化和FLI1基因的组蛋白去乙酰化上。
Objective. Scleroderma (systemic sclerosis; SSc) is an autoimmune disease characterized by vasculopathy and widespread organ fibrosis. Altered fibroblast function, both in vivo and in vitro, is well documented and illustrated by augmented synthesis and deposition of extracellular matrix proteins. We undertook this study to investigate the possibility that epigenetic mechanisms mediate the emergence and persistence of the altered SSc fibroblast phenotype.Methods. The effects of DNA methyltransferase and histone deacetylase inhibitors on collagen expression and the level of epigenetic mediators in fibroblasts were examined. The effects of transient transfection of SSc fibroblasts with FLI1 gene and normal cells with FLI1 antisense construct on collagen expression were determined. The methylation status of the FLI1 promoter was tested in cultured cells and in SSc and normal skin biopsy specimens.Results. Increased levels of epigenetic mediators in SSc fibroblasts were noted. The addition of epigenetic inhibitors to cell cultures normalized collagen expression in SSc fibroblasts. The augmented collagen synthesis by SSc fibroblasts was linked to epigenetic repression of the collagen suppressor gene FLI1 Heavy methylation of the CpG islands in the FLI1 promoter region was demonstrated in SSc fibroblasts and skin biopsy specimens.Conclusion. The results of this study indicate that epigenetic mechanisms may mediate the fibrotic manifestations of SSc. The signal transduction leading to the SSc fibrotic phenotype appears to converge on DNA methylation and histone deacetylation at the FLI1 gene.