BACKGROUND Thousands of mammalian promoters are defined by co-enrichment of the histone tail modifications H3K27me3 (repressive) and H3K4me3 (activating) and are thus termed bivalent. It was previously observed that bivalent genes in human ES cells (hESC) are frequent targets for hypermethylation in human cancers, and depletion of DNA methylation in mouse embryonic stem cells has a marked impact on H3K27me3 distribution at bivalent promoters. However, only a fraction of bivalent genes in stem cells are targets of hypermethylation in cancer, and it is currently unclear whether all bivalent promoters are equally sensitive to DNA hypomethylation and whether H3K4me3 levels play a role in the interplay between DNA methylation and H3K27me3. RESULTS We report the sub-classification of bivalent promoters into two groups-promoters with a high H3K27me3:H3K4me3 (hiBiv) ratio or promoters with a low H3K27me3:H3K4me3 ratio (loBiv). HiBiv are enriched in canonical Polycomb components, show a higher degree of local intrachromosomal contacts and are highly sensitive to DNA hypomethylation in terms of H3K27me3 depletion from broad Polycomb domains. In contrast, loBiv promoters are enriched in non-canonical Polycomb components, show lower intrachromosomal contacts and are less sensitive to DNA hypomethylation at the same genomic resolution. Multiple systems reveal that hiBiv promoters are more depleted of Polycomb complexes than loBiv promoters following a reduction in DNA methylation, and we demonstrate that H3K27me3 re-accumulates at promoters when DNA methylation is restored. In human cancer, we show that hiBiv promoters lose H3K27me3 and are more susceptible to DNA hypermethylation than loBiv promoters. CONCLUSION We conclude that bivalency as a general term to describe mammalian promoters is an over-simplification and our sub-classification has revealed novel insights into the interplay between the largely antagonistic presence of DNA methylation and Polycomb systems at bivalent promoters. This approach redefines molecular pathologies underlying disease in which global DNA methylation is aberrant or where Polycomb mutations are present.

中文翻译：

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癌症中的二价启动子高甲基化与胚胎干细胞中的 H327me3/H3K4me3 比率有关。


背景技术数以千计的哺乳动物启动子是通过组蛋白尾部修饰H3K27me3（抑制性）和H3K4me3（激活性）的共富集来定义的，因此被称为二价启动子。先前观察到，人类 ES 细胞 (hESC) 中的二价基因是人类癌症中高甲基化的常见目标，而小鼠胚胎干细胞中 DNA 甲基化的耗竭对二价启动子处的 H3K27me3 分布具有显着影响。然而，干细胞中只有一小部分二价基因是癌症中高甲基化的目标，目前尚不清楚是否所有二价启动子对 DNA 低甲基化都同样敏感，以及 H3K4me3 水平是否在 DNA 甲基化和 H3K27me3 之间的相互作用中发挥作用。结果我们报告了二价启动子分为两组：具有高 H3K27me3:H3K4me3 (hiBiv) 比率的启动子或具有低 H3K27me3:H3K4me3 比率 (loBiv) 的启动子。 HiBiv 富含典型的 Polycomb 成分，显示出更高程度的局部染色体内接触，并且在广泛的 Polycomb 结构域中去除 H3K27me3 方面对 DNA 低甲基化高度敏感。相比之下，loBiv 启动子富含非规范 Polycomb 成分，显示出较低的染色体内接触，并且在相同基因组分辨率下对 DNA 低甲基化不太敏感。多个系统表明，在 DNA 甲基化减少后，hiBiv 启动子比 loBiv 启动子更缺乏 Polycomb 复合物，并且我们证明，当 DNA 甲基化恢复时，H3K27me3 在启动子处重新积累。在人类癌症中，我们发现 hiBiv 启动子丢失了 H3K27me3，并且比 loBiv 启动子更容易受到 DNA 高甲基化的影响。 结论 我们的结论是，二价作为描述哺乳动物启动子的通用术语过于简单化，我们的子分类揭示了对二价启动子上的 DNA 甲基化和 Polycomb 系统之间的相互作用的新见解。这种方法重新定义了整体 DNA 甲基化异常或存在 Polycomb 突变的疾病的分子病理学。