Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency.
Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency.
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包括DNA去甲基化在内的表观遗传重编程发生在哺乳动物原始生殖细胞（PGCs）和早期胚胎中，对于印迹和表观变异的消除以及多能性的恢复非常重要。这种重编程的程度及其分子机制尚不清楚。我们之前的研究表明胞苷脱氨酶Aid和Apobec1可以在体外和大肠杆菌中脱氨5-甲基胞嘧啶，并且在小鼠中在发生去甲基化的组织中表达。在这里，我们通过无偏置亚硫酸盐下一代测序（BS-Seq）分析了E13.5野生型和Aid缺陷PGCs的DNA甲基化。野生型PGCs显示出显著的全基因组甲基化消除，其水平低于甲基化缺陷（Np95-/-） ES细胞，女性PGCs的甲基化程度低于男性。相比之下，Aid缺陷PGCs的甲基化程度是野生型PGCs的三倍；这种实质性的差异发生在整个基因组中，内含子、基因间区和转座子比外显子甲基化程度更高。通过基因组中单个位点的分析，证实了Aid缺陷PGCs的相对高甲基化。我们的研究结果表明，生殖系中DNA甲基化的消除是一个全球性的过程，因此限制了跨代表观遗传的可能性。Aid缺乏会干扰DNA甲基化模式的全基因组清除，这表明Aid在表观遗传重编程中具有关键功能，并可能限制哺乳动物的类聚遗传。
Epigenetic reprogramming including demethylation of DNA occurs in mammalian primordial germ cells (PGCs) and in early embryos, and is important for the erasure of imprints and epimutations, and the return to pluripotency. The extent of this reprogramming and its molecular mechanisms are poorly understood. We previously showed that the cytidine deaminases Aid and Apobec1 can deaminate 5-methylcytosine in vitro and in E coli, and in the mouse are expressed in tissues in which demethylation occurs. Here we profiled DNA methylation throughout the genome by unbiased bisulfite Next Generation Sequencing (BS-Seq) in wildtype and Aid deficient PGCs at E13.5. Wildtype PGCs revealed dramatic genome-wide erasure of methylation to a level below that of methylation deficient (Np95-/-) ES cells, with female PGCs being less methylated than male ones. By contrast, Aid deficient PGCs were up to three times more methylated than wildtype ones; this substantial difference occurred throughout the genome, with introns, intergenic regions and transposons being relatively more methylated than exons. Relative hypermethylation in Aid deficient PGCs was confirmed by analysis of individual loci in the genome. Our results reveal that erasure of DNA methylation in the germ line is a global process, hence limiting the potential for transgenerational epigenetic inheritance. Aid deficiency interferes with genome-wide erasure of DNA methylation patterns, suggesting that Aid has a critical function in epigenetic reprogramming and potentially in restricting the inheritance of epimutations in mammals.
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影响因子：
64.8
作者：
Hajkova, Petra;Ancelin, Katia;Waldmann, Tanja;Lacoste, Nicolas;Lange, Ulrike C.;Cesari, Francesca;Lee, Caroline;Almouzni, Genevieve;Schneider, Robert;Surani, M. Azim
通讯作者：
Surani, M. Azim
影响因子：
64.5
作者：
Rai K;Huggins IJ;James SR;Karpf AR;Jones DA;Cairns BR
通讯作者：
Cairns BR
DOI：
10.1126/science.1170116
发表时间：
2009-05-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Tahiliani M;Koh KP;Shen Y;Pastor WA;Bandukwala H;Brudno Y;Agarwal S;Iyer LM;Liu DR;Aravind L;Rao A
通讯作者：
Rao A
影响因子：
4.8
作者：
Morgan, HD;Dean, W;Petersen-Mahrt, SK
通讯作者：
Petersen-Mahrt, SK
DOI：
10.1073/pnas.241522698
发表时间：
2001-11-20
影响因子：
11.1
作者：
Dean, W;Santos, F;Reik, W
通讯作者：
Reik, W