Intrauterine hyperglycemia exposure results in intergenerational inheritance via DNA methylation reprogramming on F1 PGCs.
Intrauterine hyperglycemia exposure results in intergenerational inheritance via DNA methylation reprogramming on F1 PGCs.
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宫内高血糖暴露通过 F1 PGC 上的 DNA 甲基化重编程导致代际遗传
DOI：
10.1186/s13072-018-0192-2
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发表时间：
2018-05-25
影响因子：
3.9
通讯作者：
Sheng JZ
中科院分区：
文献类型：
--
作者：
Ren J;Cheng Y;Ming ZH;Dong XY;Zhou YZ;Ding GL;Pang HY;Rahman TU;Akbar R;Huang HF;Sheng JZ
背景现有关于宫内高血糖的代际或跨代影响的报道包括宫内和出生后代谢暴露因素，而宫内高血糖本身的影响尚未单独评估。许多研究表明配子的DNA甲基化重编程在代谢遗传中起着至关重要的作用，但尚不清楚当暴露于宫内高血糖时DNA甲基化模式何时以及如何改变。在这项研究中，我们选择了非糖尿病的F1和F2妊娠糖尿病（GDM）雄性小鼠作为创始人，以检查下一代的代谢变化，并对F1-GDM的第13.5天原始生殖细胞（PGCs）进行甲基化测序，以探讨潜在的表观遗传机制。和/或葡萄糖耐受不良，但在8周时F3雄性小鼠中没有代谢变化。使用还原亚硫酸氢盐测序，我们发现来自F1-GDM胎儿的13.5天PGC的DNA甲基化组显示在肥胖和糖尿病中富集的不同甲基化基因。胰岛素抵抗和脂肪积累基因Fyn的甲基化验证显示，F1 PGCs、F1胎儿睾丸、F1/C-GDM小鼠精子和F2-GDM雄性小鼠体细胞中存在一致的低甲基化状态。相比之下，没有甲基化的改变，观察F2-GDM男性生殖细胞和F3-GDM体细胞。ConclusionWe提供的证据表明，宫内高血糖暴露本身有助于代际代谢变化的F2代，但不是F3代。F1代PGCs的DNA甲基化重编程早在第13.5天就发生了。我们的研究结果表明，宫内暴露本身就足以导致F2后代的表观遗传，并且由DNA甲基化模式携带的表观遗传记忆可以被胎儿发育过程中F2 PGC的第二波甲基化重编程所消除。
BackgroundThe existing reports about intergenerational or transgenerational effects of intrauterine hyperglycemia have included both intrauterine and postnatal metabolic exposure factors, while the impact of intrauterine hyperglycemia per se has not been assessed alone. A number of studies suggest DNA methylation reprogramming of gametes plays a crucial role in the metabolic inheritance, but it is unclear when and how DNA methylation patterns are altered when exposed to intrauterine hyperglycemia. In this study, we selected nondiabetic F1- and F2-gestational diabetes mellitus (GDM) male mice as founders to examine metabolic changes in the next generation and performed methylome sequencing of day 13.5 primordial germ cells (PGCs) from F1-GDM to explore the underlying epigenetic mechanism.ResultsWe found that intrauterine hyperglycemia exposure resulted in obesity, insulin resistance, and/or glucose intolerance in F2 male mice, but no metabolic changes in F3 male mice at 8 weeks. Using reduced representation bisulfite sequencing, we found DNA methylome of day 13.5 PGCs from F1-GDM fetuses revealed differently methylated genes enriched in obesity and diabetes. Methylation validation of the insulin resistance and fat accumulation geneFynshowed a consistent hypomethylation status in F1 PGCs, F1 fetal testes, sperm from F1/C-GDM mice, and somatic cells from F2-GDM male mice. In contrast, no methylation alteration was observed in F2-GDM male germ cells and F3-GDM somatic cells.ConclusionWe provide evidence that intrauterine hyperglycemia exposure per se contributes to intergenerational metabolic changes in the F2 but not F3 generation. And the aberrant DNA methylation reprogramming occurs as early as day 13.5 in PGCs of the F1 generation. Our findings suggest that intrauterine exposure alone is sufficient to cause the epigenetic inheritance in F2 offspring, and the epigenetic memory carried by DNA methylation pattern could be erased by the second wave of methylation reprogramming in F2 PGCs during fetal development.
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影响因子：
14.9
作者：
Feng H;Conneely KN;Wu H
通讯作者：
Wu H
影响因子：
64.5
作者：
Carone BR;Fauquier L;Habib N;Shea JM;Hart CE;Li R;Bock C;Li C;Gu H;Zamore PD;Meissner A;Weng Z;Hofmann HA;Friedman N;Rando OJ
通讯作者：
Rando OJ
影响因子：
2.3
作者：
Fujii, T
通讯作者：
Fujii, T
影响因子：
7.7
作者：
Kim, Su-Jin;Nian, Cuilan;McIntosh, Christopher H. S.
通讯作者：
McIntosh, Christopher H. S.
影响因子：
64.8
作者：
Ng, Sheau-Fang;Lin, Ruby C. Y.;Morris, Margaret J.
通讯作者：
Morris, Margaret J.