Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer
Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer
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DOI：
10.1101/gr.125872.111
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发表时间：
2012-02-01
期刊：
影响因子：
7
通讯作者：
Ren, Bing
中科院分区：
文献类型：
--
作者：
Hon, Gary C.;Hawkins, R. David;Ren, Bing
虽然基因突变是癌症的标志，但许多癌症也在肿瘤发生期间获得表观遗传改变，包括肿瘤抑制因子的异常DNA超甲基化，以及由染色质修饰机制的基因突变引起的染色质修饰的变化。然而，癌细胞中表观遗传改变的程度尚未完全表征。在这里，我们描述了完整的甲基化图谱在单核苷酸分辨率的低传代乳腺癌细胞系和原代人乳腺上皮细胞。我们发现广泛的DNA低甲基化在癌细胞中，主要是在部分甲基化结构域（PMD）在正常乳腺细胞。出乎意料的是，这些区域内的基因在癌细胞中大部分被沉默。这些区域中DNA甲基化的丧失伴随着抑制性染色质的形成，其中显著部分显示等位基因DNA甲基化，其中一个等位基因被DNA甲基化，而另一个等位基因被组蛋白修饰H3K9me3或H3K27me3占据。我们的研究结果表明DNA甲基化与H3K9me3或H3K27me3之间存在互斥关系。这些结果表明，乳腺癌中的全球DNA低甲基化与抑制性染色质结构域和基因沉默的形成密切相关，从而确定了癌细胞中基因调控的潜在表观遗传途径。
While genetic mutation is a hallmark of cancer, many cancers also acquire epigenetic alterations during tumorigenesis including aberrant DNA hypermethylation of tumor suppressors, as well as changes in chromatin modifications as caused by genetic mutations of the chromatin-modifying machinery. However, the extent of epigenetic alterations in cancer cells has not been fully characterized. Here, we describe complete methylome maps at single nucleotide resolution of a low-passage breast cancer cell line and primary human mammary epithelial cells. We find widespread DNA hypomethylation in the cancer cell, primarily at partially methylated domains (PMDs) in normal breast cells. Unexpectedly, genes within these regions are largely silenced in cancer cells. The loss of DNA methylation in these regions is accompanied by formation of repressive chromatin, with a significant fraction displaying allelic DNA methylation where one allele is DNA methylated while the other allele is occupied by histone modifications H3K9me3 or H3K27me3. Our results show a mutually exclusive relationship between DNA methylation and H3K9me3 or H3K27me3. These results suggest that global DNA hypomethylation in breast cancer is tightly linked to the formation of repressive chromatin domains and gene silencing, thus identifying a potential epigenetic pathway for gene regulation in cancer cells.