胚系 DNA 去甲基化动力学和印迹消除通过 5-羟甲基胞嘧啶。
Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine.
机构信息
Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, CB2 1QN, United Kingdom.
Wellcome Trust/MRC Stem Cell Institute, University of Cambridge, Cambridge, UK.
出版信息
Science. 2013 Jan 25;339(6118):448-52. doi: 10.1126/science.1229277. Epub 2012 Dec 6.
Abstract
Mouse primordial germ cells (PGCs) undergo sequential epigenetic changes and genome-wide DNA demethylation to reset the epigenome for totipotency. Here, we demonstrate that erasure of CpG methylation (5mC) in PGCs occurs via conversion to 5-hydroxymethylcytosine (5hmC), driven by high levels of TET1 and TET2. Global conversion to 5hmC initiates asynchronously among PGCs at embryonic day (E) 9.5 to E10.5 and accounts for the unique process of imprint erasure. Mechanistically, 5hmC enrichment is followed by its protracted decline thereafter at a rate consistent with replication-coupled dilution. The conversion to 5hmC is an important component of parallel redundant systems that drive comprehensive reprogramming in PGCs. Nonetheless, we identify rare regulatory elements that escape systematic DNA demethylation in PGCs, providing a potential mechanistic basis for transgenerational epigenetic inheritance.
摘要
小鼠原始生殖细胞（PGC）经历连续的表观遗传变化和全基因组 DNA 去甲基化，以重置全能性的表观基因组。在这里，我们证明 PGC 中的 CpG 甲基化（5mC）的消除是通过高水平的 TET1 和 TET2 驱动的向 5-羟甲基胞嘧啶（5hmC）的转化来实现的。全局向 5hmC 的转化在胚胎日（E）9.5 至 E10.5 期间在 PGC 中异步发生，并解释了印迹消除的独特过程。从机制上讲，5hmC 的富集随后以与其复制偶联稀释一致的速率持续下降。向 5hmC 的转化是驱动 PGC 中全面重编程的并行冗余系统的重要组成部分。尽管如此，我们鉴定了在 PGC 中逃避系统 DNA 去甲基化的罕见调控元件，为跨代表观遗传遗传提供了潜在的机制基础。
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