Bivalent Regions of Cytosine Methylation and H3K27 Acetylation Suggest an Active Role for DNA Methylation at Enhancers.
Bivalent Regions of Cytosine Methylation and H3K27 Acetylation Suggest an Active Role for DNA Methylation at Enhancers.
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DOI：
10.1016/j.molcel.2016.03.033
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发表时间：
2016-05-05
期刊：
影响因子：
16
通讯作者：
Jones PA
中科院分区：
文献类型：
--
作者：
Charlet J;Duymich CE;Lay FD;Mundbjerg K;Dalsgaard Sørensen K;Liang G;Jones PA
胞嘧啶甲基化在增强子结构和功能中的作用还不清楚。在这项研究中，我们通过比较HCT 116细胞系及其高度去甲基化衍生物DKO 1的表观基因组来研究DNA甲基化在增强子中的作用。与启动子不同，一部分常规和“超级”或“延伸”增强子显示活性H3 K27 ac标记与广泛的DNA甲基化共存，证明了培养和未培养细胞中“二价染色质”的意外存在。此外，我们的研究结果还表明，二价区有更少的核小体耗尽区和转录因子结合位点比单价区。DNA甲基化的减少会导致H3 K27 ac标记的减少。因此，DNA甲基化在增强子区域起着意想不到的双重作用，在转录因子结合位点局部反相关，但与活性H3 K27 ac标记整体正相关，以确保结构增强子的完整性。增强子的表观遗传景观具有意想不到的特征;常规和超级增强子在其染色质结构中可以是二价的，在相同的核小体上携带活性H3 K27 ac和抑制性DNA甲基化标记。与单价增强子不同，这些二价区域通过DNA甲基化来稳定，并且可能需要DNA甲基化来潜在地保持活性。
The role of cytosine methylation in the structure and function of enhancers is not well understood. In this study, we investigate the role of DNA methylation at enhancers by comparing the epigenomes of the HCT116 cell line and its highly demethylated derivative, DKO1. Unlike promoters, a portion of regular and “super-” or “stretch” enhancers show active H3K27ac marks co-existing with extensive DNA methylation, demonstrating the unexpected presence of “bivalent chromatin” in both cultured and uncultured cells. Furthermore, our findings also show that bivalent regions have fewer nucleosome-depleted regions and transcription factor binding sites than monovalent regions. Reduction of DNA methylation genetically or pharmacologically leads to a decrease of the H3K27ac mark. Thus DNA methylation plays an unexpected dual role at enhancer regions, being anti-correlated focally at transcription factor binding sites but positively correlated globally with the active H3K27ac mark to ensure structural enhancer integrity. The epigenetic landscape of enhancers has an unexpected characteristic; both regular and super-enhancers can be bivalent in their chromatin structures, carrying active H3K27ac and repressive DNA methylation marks on the same nucleosomes. Unlike monovalent enhancers, these bivalent regions are stabilized by and may require DNA methylation to potentially remain active.