An annotated list of bivalent chromatin regions in human ES cells: a new tool for cancer epigenetic research.
An annotated list of bivalent chromatin regions in human ES cells: a new tool for cancer epigenetic research.
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DOI：
10.18632/oncotarget.13746
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发表时间：
2017-01-17
期刊：
影响因子：
--
通讯作者：
Arnaud P
中科院分区：
文献类型：
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作者：
Court F;Arnaud P
干细胞中由二价染色质标记的CpG岛（CGI）被认为更容易在肿瘤细胞中发生异常DNA甲基化。这种指导性计划在不同癌症类型中的稳健性和全基因组范围仍有待确定。为了解决这个问题，我们开发了一种用户友好的方法，将干细胞染色质特征整合到定制的DNA甲基化分析中。我们使用公开的几种人胚胎干细胞（hESC）系的ChIP测序数据集来确定全基因组二价染色质的程度。然后，我们创建了高置信度二价、仅H3 K4 me 3和仅H3 K27 me 3染色质区域的注释列表。二价区的主要特征包括CGI/启动子的定位、逆转录元件的缺失和特异性组蛋白修饰的富集，包括表征不佳的H3 K23 me 2标记。此外，二价启动子可以分为三个集群的基础上PRC 2和PolII复合物占用。具有PRC 2定义的簇的二价启动子的基因在分化时显示最低表达。作为概念验证，我们评估了八种类型肿瘤的DNA甲基化模式，并证实异常癌症相关的DNA超甲基化优先靶向hESC中以二价染色质为特征的CGI。我们还发现，这种异常的DNA超甲基化特别影响与分化后倾向于保持抑制的基因相关的二价CGI/启动子。引人注目的是，在CpG岛甲基化表型阳性（CIMP+）和CIMP阴性肿瘤中，二价CGI受异常DNA超甲基化的影响最大，这表明，除了在致瘤前细胞中的转录沉默之外，hESC中的二价染色质特征是异常DNA甲基化的指导性程序的关键决定因素。
CpG islands (CGI) marked by bivalent chromatin in stem cells are believed to be more prone to aberrant DNA methylation in tumor cells. The robustness and genome-wide extent of this instructive program in different cancer types remain to be determined. To address this issue we developed a user-friendly approach to integrate the stem cell chromatin signature in customized DNA methylation analyses. We used publicly available ChIP-sequencing datasets of several human embryonic stem cell (hESC) lines to determine the extent of bivalent chromatin genome-wide. We then created annotated lists of high-confidence bivalent, H3K4me3-only and H3K27me3-only chromatin regions. The main features of bivalent regions included localization in CGI/promoters, depletion in retroelements and enrichment in specific histone modifications, including the poorly characterized H3K23me2 mark. Moreover, bivalent promoters could be classified in three clusters based on PRC2 and PolII complexes occupancy. Genes with bivalent promoters of the PRC2-defined cluster displayed the lowest expression upon differentiation. As proof-of-concept, we assessed the DNA methylation pattern of eight types of tumors and confirmed that aberrant cancer-associated DNA hypermethylation preferentially targets CGI characterized by bivalent chromatin in hESCs. We also found that such aberrant DNA hypermethylation affected particularly bivalent CGI/promoters associated with genes that tend to remain repressed upon differentiation. Strikingly, bivalent CGI were the most affected by aberrant DNA hypermethylation in both CpG Island Methylator Phenotype-positive (CIMP+) and CIMP-negative tumors, suggesting that, besides transcriptional silencing in the pre-tumorigenic cells, the bivalent chromatin signature in hESCs is a key determinant of the instructive program for aberrant DNA methylation.