Changes of bivalent chromatin coincide with increased expression of developmental genes in cancer
Changes of bivalent chromatin coincide with increased expression of developmental genes in cancer
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DOI：
10.1038/srep37393
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发表时间：
2016-11-23
影响因子：
4.6
通讯作者：
Hoffmann, Steve
中科院分区：
文献类型：
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作者：
Bernhart, Stephan H.;Kretzmer, Helene;Hoffmann, Steve
二价（平衡或暂停）染色质包括在相同位置激活和抑制组蛋白修饰。在启动子或增强子区域的表观遗传标记的这种组合使基因以低水平表达，但准备快速激活。通常，二价启动子处的DNA在正常细胞中仅低甲基化，但在癌症样品中经常显示升高的甲基化水平。在这里，我们开发了一个通用的分类器，建立从染色质数据，可以识别癌症样本仅从二价染色质的超甲基化。在几种癌症类型的7,000多个DNA甲基化数据集上进行测试，其AUC达到0.92。虽然较高水平的DNA甲基化通常与转录沉默相关，但最近报道了两种癌症类型的DNA甲基化和表达水平之间的反直觉正统计依赖性。在这里，我们重新分析了组合的表达和DNA甲基化数据集，包括超过5,000个样本，并证明了二价染色质的超甲基化和相应基因的上调是癌症中的普遍现象。这种上调影响许多发育基因和转录因子，包括数十个同源异型盒基因和其他与癌症有关的基因。因此，我们推断二价染色质的紊乱可能与肿瘤发生密切相关。
Bivalent (poised or paused) chromatin comprises activating and repressing histone modifications at the same location. This combination of epigenetic marks at promoter or enhancer regions keeps genes expressed at low levels but poised for rapid activation. Typically, DNA at bivalent promoters is only lowly methylated in normal cells, but frequently shows elevated methylation levels in cancer samples. Here, we developed a universal classifier built from chromatin data that can identify cancer samples solely from hypermethylation of bivalent chromatin. Tested on over 7,000 DNA methylation data sets from several cancer types, it reaches an AUC of 0.92. Although higher levels of DNA methylation are often associated with transcriptional silencing, counter-intuitive positive statistical dependencies between DNA methylation and expression levels have been recently reported for two cancer types. Here, we re-analyze combined expression and DNA methylation data sets, comprising over 5,000 samples, and demonstrate that the conjunction of hypermethylation of bivalent chromatin and up-regulation of the corresponding genes is a general phenomenon in cancer. This up-regulation affects many developmental genes and transcription factors, including dozens of homeobox genes and other genes implicated in cancer. Thus, we reason that the disturbance of bivalent chromatin may be intimately linked to tumorigenesis.