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Genome-scale DNA methylation maps of pluripotent and differentiated cells

机译：多能和分化细胞的基因组规模DNA甲基化图

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DNA methylation is essential for normal development and has been implicated in many pathologies including cancer. Our knowledge about the genome-wide distribution of DNA methylation, how it changes during cellular differentiation and how it relates to histone methylation and other chromatin modifications in mammals remains limited. Here we report the generation and analysis of genome-scale DNA methylation profiles at nucleotide resolution in mammalian cells. Using high-throughput reduced representation bisulphite sequencing6 and single-molecule-based sequencing, we generated DNA methylation maps covering most CpG islands, and a representative sampling of conserved non-coding elements, transposons and other genomic features, for mouse embryonic stem cells, embryonic-stem-cell-derived and primary neural cells, and eight other primary tissues. Several key findings emerge from the data. First, DNA methylation patterns are better correlated with histone methylation patterns than with the underlying genome sequence context. Second, methylation of CpGs are dynamic epigenetic marks that undergo extensive changes during cellular differentiation, particularly in regulatory regions outside of core promoters. Third, analysis of embryonic-stem-cell-derived and primary cells reveals that 'weak' CpG islands associated with a specific set of developmentally regulated genes undergo aberrant hypermethylation during extended proliferation in vitro, in a pattern reminiscent of that reported in some primary tumours. More generally, the results establish reduced representation bisulphite sequencing as a powerful technology for epigenetic profiling of cell populations relevant to developmental biology, cancer and regenerative medicine.
机译：DNA甲基化对于正常发育必不可少，并且已牵涉到许多病理学，包括癌症。我们对DNA甲基化的全基因组分布，其在细胞分化过程中如何变化以及与哺乳动物中的组蛋白甲基化和其他染色质修饰之间的关系的了解仍然有限。在这里，我们报告了在哺乳动物细胞中以核苷酸分辨率进行的基因组规模DNA甲基化分布图的生成和分析。使用高通量还原代表性亚硫酸氢盐测序6和基于单分子的测序，我们生成了涵盖大多数CpG岛的DNA甲基化图谱，以及用于小鼠胚胎干细胞，胚胎的保守非编码元件，转座子和其他基因组特征的代表性样本干细胞和原代神经细胞，以及其他八种原代组织。从数据中得出一些关键发现。首先，DNA甲基化模式与组蛋白甲基化模式的关联比与基础基因组序列的关联更好。其次，CpG的甲基化是动态表观遗传标记，在细胞分化过程中会发生广泛的变化，特别是在核心启动子之外的调控区域。第三，对胚胎干细胞和原代细胞的分析表明，与特定的一组发育调控基因相关的“弱” CpG岛在体外延长的增殖过程中经历了异常的高甲基化，这种模式让人联想到一些原发性肿瘤中报道的模式。 。更普遍地，结果建立了减少的代表性亚硫酸氢盐测序，作为与发育生物学，癌症和再生医学有关的细胞群的表观遗传概况分析的有力技术。

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