Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.
Nature. 2011 Dec 14;480(7378):490-5. doi: 10.1038/nature10716.
Methylation of cytosines is an essential epigenetic modification in mammalian genomes, yet the rules that govern methylation patterns remain largely elusive. To gain insights into this process, we generated base-pair-resolution mouse methylomes in stem cells and neuronal progenitors. Advanced quantitative analysis identified low-methylated regions (LMRs) with an average methylation of 30%. These represent CpG-poor distal regulatory regions as evidenced by location, DNase I hypersensitivity, presence of enhancer chromatin marks and enhancer activity in reporter assays. LMRs are occupied by DNA-binding factors and their binding is necessary and sufficient to create LMRs. A comparison of neuronal and stem-cell methylomes confirms this dependency, as cell-type-specific LMRs are occupied by cell-type-specific transcription factors. This study provides methylome references for the mouse and shows that DNA-binding factors locally influence DNA methylation, enabling the identification of active regulatory regions.
胞嘧啶甲基化是哺乳动物基因组中一种重要的表观遗传修饰，但控制甲基化模式的规则在很大程度上仍难以捉摸。为了深入了解这一过程，我们在干细胞和神经祖细胞中生成了碱基对分辨率的小鼠甲基组。高级定量分析鉴定出平均甲基化水平为 30%的低甲基化区域（LMR）。这些区域作为 CpG 贫乏的远端调控区域存在，这一点可以从位置、DNase I 超敏反应、增强子染色质标记和报告基因检测中的增强子活性得到证明。LMR 被 DNA 结合因子占据，其结合对于创建 LMR 是必要和充分的。神经元和干细胞甲基组的比较证实了这种依赖性，因为细胞类型特异性的 LMR 被细胞类型特异性的转录因子占据。这项研究为小鼠提供了甲基组参考，并表明 DNA 结合因子局部影响 DNA 甲基化，从而能够识别活跃的调控区域。
