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出现于哺乳动物早期胚胎中的一种独特DNA甲基化调整阶段
对于哺乳动物,受精后,基因组发生了一次广谱性的去甲基化过程。精子进入卵细胞后,立即发生主动去甲基化,随后在卵裂过程中,卵子的基因组发生被动的去甲基化。进入囊胚期,基因组的甲基化达到相当低的水平。之后,随着个体的发育,多潜能基因被甲基化,不同类型的细胞建立起不同的DNA甲基化谱,使之具有不同的表达模式。这种模式是我们现在普遍认识的哺乳动物基因组甲基化动态变化趋势。可是,支持这种模式的数据至今仍然不足,没有高分辨率的图谱。本研究中,科学家通过RRBS测序技术,构建了小鼠受精后配子的DNA甲基化图谱。结果发现,卵母细胞较早就呈显整体水平的低甲基化状态,特别对于长散在元件1和长末端重复反转录因子具有更低的甲基化水平。更为惊奇的是,卵母细胞有一个独特的差异甲基化区(DMRs),主要包含CpG岛富集的启动子,它存在于早期的胚胎细胞中,体细胞中则缺失。相反,精细胞来源的DMRs主要位于基因间,囊胚期后即被高度甲基化。结论,本实验构建了一个表观遗传修饰动态变化最强时期胚胎的基因组高分辨率DNA甲基化图,并发现了一个与先前研究不同的甲基化变化趋势。本研究为探究DNA甲基化的基本机制和调控原理,以及它们在胚胎发育过程中的功能提供了一个新的思路。
Abstract
DNA methylation is highly dynamic during mammalian embryogenesis. It is broadly accepted that the paternal genome is actively depleted of 5-methylcytosine at fertilization, followed by passive loss that reaches a minimum at the blastocyst stage. However, this model is based on limited data, and so far no base-resolution maps exist to support and refine it. Here we generate genome-scale DNA methylation maps in mouse gametes and from the zygote through post-implantation. We find that the oocyte already exhibits global hypomethylation, particularly at specific families of long interspersed element 1 and long terminal repeat retroelements, which are disparately methylated between gametes and have lower methylation values in the zygote than in sperm. Surprisingly, the oocyte contributes a unique set of differentially methylated regions (DMRs)-including many CpG island promoters-that are maintained in the early embryo but are lost upon specification and absent from somatic cells. In contrast, sperm-contributed DMRs are largely intergenic and become hypermethylated after the blastocyst stage. Our data provide a genome-scale, base-resolution timeline of DNA methylation in the pre-specified embryo, when this epigenetic modification is most dynamic, before returning to the canonical somatic pattern.
原文:A unique regulatory phase of DNA methylation in the early mammalian embryo. Nature. 2012.
编辑: gaowei2010