SWI/SNF chromatin-remodeling factors induce changes in DNA methylation to promote transcriptional activation
SWI/SNF chromatin-remodeling factors induce changes in DNA methylation to promote transcriptional activation
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DOI：
10.1158/0008-5472.can-04-3554
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发表时间：
2005-05-01
期刊：
影响因子：
11.2
通讯作者：
Sherman, LS
中科院分区：
文献类型：
--
作者：
Banine, F;Bartlett, C;Sherman, LS
Brahma（Brm）和Brahma相关基因1（Brg1）是SWI/SNF染色质重塑因子亚基的哺乳动物同源物，它们能够调节转录激活和抑制。在许多癌细胞系中，Brg1和Brm都发生突变或缺失，导致影响细胞增殖和转移的基因表达改变。在此，我们发现两个此类基因（CD44和E - 钙黏蛋白）的启动子在缺失Brg1或Brm的细胞中发生高甲基化。在两个缺乏功能性Brg1和Brut的癌细胞系中，去甲基化试剂5 - 氮杂 - 2'- 脱氧胞苷可诱导CD44和E - 钙黏蛋白的表达。在这些细胞中，转染Brg1或Brm也可诱导CD44和E - 钙黏蛋白的转录及蛋白质表达，同时两个基因启动子序列的甲基化缺失。染色质免疫沉淀分析表明，Brg1和Brm与CD44和E - 钙黏蛋白启动子的这些区域相关联，这表明SWI/SNF蛋白复合物可能直接影响DNA甲基化的缺失。在体内，Brm缺陷型小鼠也显示出CD44启动子的甲基化和沉默。总之，这些数据表明SWI/SNF介导的转录激活缺失是癌细胞中DNA甲基化增加的一种新机制，并为肿瘤进展过程中异常基因诱导和抑制的潜在机制提供了见解。
Brahma (Brm) and brahma-related gene-1 (Brg1) are mammalian homologues of SWI/SNF chromatin-remodeling factor subunits that can regulate both transcriptional activation and repression. Both Brg1 and Brm are mutated or deleted in numerous cancer cell lines, leading to the altered expression of genes that influence cell proliferation and metastasis. Here, we find that the promoters of two such genes, CD44 and E-cadherin, are hypermethylated in cells that have lost Brg1 or Brm. In two carcinoma cell lines that lack functional Brg1 and Brut, CD44 and E-cadherin expression are induced by the demethylating agent 5-aza-2'-deoxycytidine. Transfection with either Brg1 or Brm also induces CD44 and E-cadherin transcription and protein expression in these cells, as we as loss of methylation at sequences in the promoters of both genes. Chromatin immunoprecipitation assays show that Brg1 and Brm associate with these regions of the CD44 and E-cadherin promoters, suggesting that SWI/SNF protein complexes may directly influence the loss of DNA methylation. In vivo, Brm-deficient mice also show methylation and silencing of the CD44 promoter. Collectively, these data implicate loss of SWI/SNF-mediated transcriptional activation as a novel mechanism to increase DNA methylation in cancer cells and provide insight into the mechanisms underlying aberrant gene induction and repression during tumor progression.