Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer.
Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer.
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DOI：
10.1186/s13059-016-0879-2
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发表时间：
2016-01-26
期刊：
影响因子：
12.3
通讯作者：
Esteller M
中科院分区：
文献类型：
--
作者：
Heyn H;Vidal E;Ferreira HJ;Vizoso M;Sayols S;Gomez A;Moran S;Boque-Sastre R;Guil S;Martinez-Cardus A;Lin CY;Royo R;Sanchez-Mut JV;Martinez R;Gut M;Torrents D;Orozco M;Gut I;Young RA;Esteller M
癌症的标志之一是基因表达模式的破坏。许多分子损伤导致这种表型，并且异常DNA甲基化谱的重要性越来越被认识到。在这一领域的许多研究工作已经检查了近端启动子区域，而在其他位点的表观遗传学改变还没有得到很好的表征。使用全基因组亚硫酸氢盐测序来检查表观基因组的未知区域，我们确定了一种类型的癌细胞中的远端调控序列的深远的DNA甲基化改变，被描述为超级增强子。人类肿瘤发生了超增强子DNA甲基化谱的转变，这与相应靶基因的转录沉默或过度激活有关。有趣的是，我们观察到局部活性部分的超级增强子检测通过低甲基化区域，这表明大的增强子簇内的空间变异性。在功能上，获得的DNA甲基化组表明，转录因子有助于这种局部活性的超级增强子和反式作用因子调节DNA甲基化谱的影响，在癌变过程中的转化过程。我们开发了一个广泛的人类DNA甲基化的目录在碱基分辨率，以更好地了解DNA甲基化的调控功能以外的近端启动子基因区域。正常细胞中的CpG甲基化状态指向超级增强子处的局部活性调节位点，其被癌症中的特定异常DNA甲基化事件靶向，对下游基因的表达具有推定的影响。本文的在线版本（doi：10.1186/s13059-016-0879-2）包含补充材料，可供授权用户使用。
One of the hallmarks of cancer is the disruption of gene expression patterns. Many molecular lesions contribute to this phenotype, and the importance of aberrant DNA methylation profiles is increasingly recognized. Much of the research effort in this area has examined proximal promoter regions and epigenetic alterations at other loci are not well characterized. Using whole genome bisulfite sequencing to examine uncharted regions of the epigenome, we identify a type of far-reaching DNA methylation alteration in cancer cells of the distal regulatory sequences described as super-enhancers. Human tumors undergo a shift in super-enhancer DNA methylation profiles that is associated with the transcriptional silencing or the overactivation of the corresponding target genes. Intriguingly, we observe locally active fractions of super-enhancers detectable through hypomethylated regions that suggest spatial variability within the large enhancer clusters. Functionally, the DNA methylomes obtained suggest that transcription factors contribute to this local activity of super-enhancers and that trans-acting factors modulate DNA methylation profiles with impact on transforming processes during carcinogenesis. We develop an extensive catalogue of human DNA methylomes at base resolution to better understand the regulatory functions of DNA methylation beyond those of proximal promoter gene regions. CpG methylation status in normal cells points to locally active regulatory sites at super-enhancers, which are targeted by specific aberrant DNA methylation events in cancer, with putative effects on the expression of downstream genes. The online version of this article (doi:10.1186/s13059-016-0879-2) contains supplementary material, which is available to authorized users.