In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism.
In utero effects. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism.
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DOI：
10.1126/science.1255903
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发表时间：
2014-08-15
期刊：
影响因子：
--
通讯作者：
Ferguson-Smith AC
中科院分区：
文献类型：
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作者：
Radford EJ;Ito M;Shi H;Corish JA;Yamazawa K;Isganaitis E;Seisenberger S;Hore TA;Reik W;Erkek S;Peters AHFM;Patti ME;Ferguson-Smith AC
不良的产前环境会促进后代和后代的代谢疾病。动物模型和流行病学数据暗示表观遗传，但机制仍然未知。在影响F2代谢的代际发育规划模型中，我们证明了F1胚胎的子宫内营养环境以基因座特异性的方式改变了F1成年男性的生殖系DNA甲基化组。差异甲基化的区域是低甲基化的，并且在核小体保留区富集。很大一部分对早期胚胎甲基化重编程具有抗性，可能影响F2的发育。重要的是，差异甲基化不维持在F2组织中，但基因座特异性表达受到干扰。因此，在生殖细胞发育的关键窗口期间的子宫内营养暴露可影响与后代代谢疾病相关的雄性生殖系甲基化组。
Adverse prenatal environments can promote metabolic disease in offspring and subsequent generations. Animal models and epidemiological data implicate epigenetic inheritance but mechanisms remain unknown. In an intergenerational developmental programming model affecting F2 metabolism, we demonstrate that the in utero nutritional environment of F1 embryos alters the germline DNA methylome of F1 adult males in a locus-specific manner. Differentially methylated regions are hypomethylated and enriched in nucleosome-retaining regions. A substantial fraction is resistant to early embryo methylation reprogramming, potentially impacting F2 development. Importantly, differential methylation is not maintained in F2 tissues, yet locus-specific expression is perturbed. Thus, in utero nutritional exposures during critical windows of germ cell development can impact the male germline methylome, associated with metabolic disease in offspring.