Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Cell Res. 2010 Nov;20(11):1201-15. doi: 10.1038/cr.2010.128. Epub 2010 Sep 7.
Global DNA hypomethylation at CpG islands coupled with local hypermethylation is a hallmark for breast cancer, yet the mechanism underlying this change remains elusive. In this study, we showed that DNMT1, which encodes a methylation maintenance enzyme, is a transcriptional target of BRCA1. BRCA1 binds to the promoter of the DNMT1 gene through a potential OCT1 site and the binding is required for maintaining a transcriptional active configuration of the promoter in both mouse and human cells. We further demonstrated that impaired function of BRCA1 leads to global DNA hypomethylation, loss of genomic imprinting, and an open chromatin configuration in several types of tissues examined in a BRCA1 mutant mouse model at premaligant stages. BRCA1 deficiency is also associated with significantly increased expression levels of several protooncogenes, including c-Fos, Ha-Ras, and c-Myc, with a higher expression in tumors, while premalignant mammary epithelial cells displayed an intermediate state between tumors and controls. In human clinical samples, reduced expression of BRCA1 correlates with decreased levels of DNMT1, and reduced methylation of CpG islands. Thus, BRCA1 prevents global DNA hypomethylation through positively regulating DNMT1 expression, and this provides one of mechanisms for BRCA1-associated breast cancer formation.
全球 CpG 岛的 DNA 低甲基化与局部高甲基化是乳腺癌的一个标志，但这种变化的机制仍难以捉摸。在这项研究中，我们表明，编码甲基化维持酶的 DNMT1 是 BRCA1 的转录靶标。BRCA1 通过潜在的 OCT1 位点与 DNMT1 基因的启动子结合，该结合对于在小鼠和人细胞中维持启动子的转录活性构象是必需的。我们进一步证明，BRCA1 功能障碍导致几种组织类型的全局 DNA 低甲基化、基因组印迹丧失和开放染色质构象，在早发性癌变阶段的 BRCA1 突变小鼠模型中进行了检查。BRCA1 缺乏还与几种原癌基因（包括 c-Fos、Ha-Ras 和 c-Myc）的表达水平显著增加相关，在肿瘤中表达水平更高，而早发性乳腺上皮细胞显示出介于肿瘤和对照之间的中间状态。在人类临床样本中，BRCA1 的表达降低与 DNMT1 水平降低和 CpG 岛甲基化降低相关。因此，BRCA1 通过正向调节 DNMT1 的表达来防止全局 DNA 低甲基化，这为 BRCA1 相关乳腺癌的形成提供了一种机制。
