Genome-wide bisulfite sequencing in zygotes identifies demethylation targets and maps the contribution of TET3 oxidation.
Genome-wide bisulfite sequencing in zygotes identifies demethylation targets and maps the contribution of TET3 oxidation.
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DOI：
10.1016/j.celrep.2014.11.034
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发表时间：
2014-12-24
期刊：
影响因子：
8.8
通讯作者：
Reik W
中科院分区：
文献类型：
--
作者：
Peat JR;Dean W;Clark SJ;Krueger F;Smallwood SA;Ficz G;Kim JK;Marioni JC;Hore TA;Reik W
受精触发父亲的5-甲基胞嘧啶的整体擦除作为从配子特化到全能性过渡期间的表观遗传重编程的一部分。这涉及TET 3的氧化，但我们对其靶点和更广泛的去甲基化背景的理解仅限于基因组的一小部分。我们采用了优化的亚硫酸氢盐策略来生成对照和TET 3缺陷合子的全基因组甲基化谱，使用SNP来访问父系等位基因。这表明，除了普遍删除从基因间序列和大多数反转录转座子，基因体构成合子去甲基化的主要目标。甲基化缺失与合子基因组激活有关，并且在基因体上也与早期发育中增加的转录噪音有关。我们的数据映射的主要贡献的氧化去甲基化的基因体和基因间序列的子集，并牵连在许多位点的冗余途径。出乎意料的是，我们证明TET 3活性也保护某些CpG岛免受甲基化积累。增强的亚硫酸氢盐策略允许合子的全基因组甲基化分析基因体构成合子去甲基化和TET 3氧化的主要靶点TET 3丢失的影响是中等的，并且涉及冗余的去甲基化途径保护性TET 3活性保护某些CpG岛免受甲基化积累Peat et al.采用全基因组亚硫酸氢盐测序，以生成由受精触发的深刻DNA甲基化重编程的全局图像。这将基因体鉴定为主要的去甲基化靶标，其中TET 3氧化起重要作用，并揭示了保护性TET 3功能以及去甲基化机制中的冗余。
Fertilization triggers global erasure of paternal 5-methylcytosine as part of epigenetic reprogramming during the transition from gametic specialization to totipotency. This involves oxidation by TET3, but our understanding of its targets and the wider context of demethylation is limited to a small fraction of the genome. We employed an optimized bisulfite strategy to generate genome-wide methylation profiles of control and TET3-deficient zygotes, using SNPs to access paternal alleles. This revealed that in addition to pervasive removal from intergenic sequences and most retrotransposons, gene bodies constitute a major target of zygotic demethylation. Methylation loss is associated with zygotic genome activation and at gene bodies is also linked to increased transcriptional noise in early development. Our data map the primary contribution of oxidative demethylation to a subset of gene bodies and intergenic sequences and implicate redundant pathways at many loci. Unexpectedly, we demonstrate that TET3 activity also protects certain CpG islands against methylation buildup. An enhanced bisulfite strategy allows genome-wide methylation profiling of zygotes Gene bodies constitute a major target of zygotic demethylation and TET3 oxidation The impact of TET3 loss is moderate and implicates redundant demethylation pathways Protective TET3 activity shields certain CpG islands against methylation buildup Peat et al. employ whole-genome bisulfite sequencing to generate a global picture of the profound DNA methylation reprogramming that is triggered by fertilization. This identifies gene bodies as a major demethylation target where TET3 oxidation plays an important role and uncovers a protective TET3 function as well as redundancy in the demethylation machinery.