DNA methylation prevents CTCF-mediated silencing of the oncogene BCL6 in B cell lymphomas.
DNA methylation prevents CTCF-mediated silencing of the oncogene BCL6 in B cell lymphomas.
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DOI：
10.1084/jem.20100204
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发表时间：
2010-08-30
期刊：
影响因子：
--
通讯作者：
Wade PA
中科院分区：
文献类型：
--
作者：
Lai AY;Fatemi M;Dhasarathy A;Malone C;Sobol SE;Geigerman C;Jaye DL;Mav D;Shah R;Li L;Wade PA
异常的DNA甲基化通常发生在癌细胞中，其中它与肿瘤抑制基因的表观遗传沉默有关。DNA甲基化的其他作用，如转录激活，已被预测，但尚未得到明确证明。BCL 6癌基因与生发中心来源的B细胞淋巴瘤的发病机制有关。我们证明，人类BCL 6基因座的第一个内含子内的基因内CpG岛在表达大量BCL 6信使RNA（mRNA）的淋巴瘤细胞中被高甲基化。DNA甲基转移酶的抑制降低了BCL 6 mRNA的丰度，这表明这些甲基化的CpG在正调控BCL 6转录中的作用。增强子阻断转录因子CTCF以甲基化敏感的方式与该内含子区域结合。在不表达BCL 6的肿瘤性浆细胞中，短发夹RNA消耗CTCF导致BCL 6转录上调。这些数据表明，在淋巴瘤发生过程中，BCL 6的表达部分通过DNA甲基化来维持，DNA甲基化阻止了CTCF介导的沉默。
Aberrant DNA methylation commonly occurs in cancer cells where it has been implicated in the epigenetic silencing of tumor suppressor genes. Additional roles for DNA methylation, such as transcriptional activation, have been predicted but have yet to be clearly demonstrated. The BCL6 oncogene is implicated in the pathogenesis of germinal center–derived B cell lymphomas. We demonstrate that the intragenic CpG islands within the first intron of the human BCL6 locus were hypermethylated in lymphoma cells that expressed high amounts of BCL6 messenger RNA (mRNA). Inhibition of DNA methyltransferases decreased BCL6 mRNA abundance, suggesting a role for these methylated CpGs in positively regulating BCL6 transcription. The enhancer-blocking transcription factor CTCF bound to this intronic region in a methylation-sensitive manner. Depletion of CTCF by short hairpin RNA in neoplastic plasma cells that do not express BCL6 resulted in up-regulation of BCL6 transcription. These data indicate that BCL6 expression is maintained during lymphomagenesis in part through DNA methylation that prevents CTCF-mediated silencing.
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