Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
J Exp Med. 2010 Aug 30;207(9):1939-50. doi: 10.1084/jem.20100204. Epub 2010 Aug 23.
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.
异常的 DNA 甲基化在癌细胞中很常见，它被认为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，已经被预测，但尚未得到明确证实。BCL6 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，在表达大量 BCL6 信使 RNA（mRNA）的淋巴瘤细胞中，人类 BCL6 基因座第一个内含子内的基因内 CpG 岛被高度甲基化。抑制 DNA 甲基转移酶会降低 BCL6 mRNA 的丰度，这表明这些甲基化的 CpG 可能在正向调节 BCL6 转录中发挥作用。增强子阻断转录因子 CTCF 以甲基化敏感的方式结合到这个内含子区域。在不表达 BCL6 的肿瘤浆细胞中用短发夹 RNA 耗尽 CTCF 会导致 BCL6 转录的上调。这些数据表明，BCL6 的表达在淋巴瘤发生过程中部分是通过 DNA 甲基化维持的，这种甲基化阻止了 CTCF 介导的沉默。
