Vitamin B12 deficiency is a critical problem worldwide and peri-conceptional deficiency of this vitamin is associated with the risk of complex cardio-metabolic diseases. Nutritional perturbations during these stages of development may lead to changes in the fetal epigenome. Using Wistar rat model system, we have earlier shown that low maternal B12 levels are associated with low birth weight, adiposity, insulin resistance, and increased triglyceride levels in the offspring, which might predispose them to the risk of cardio-metabolic diseases in adulthood. In this study, we have investigated the effects of maternal B12 deficiency on genome-wide DNA methylation profile of the offspring and the effect of rehabilitation of mothers with B12 at conception. We have performed methylated DNA immunoprecipitation sequencing of liver from pups in four groups of Wistar rats: Control (C), B12-restricted (B12R), B12-rehabilitated at conception (B12RC), and B12-rehabilitated at parturition (B12RP). We have analyzed differentially methylated signatures between the three groups as compared to controls. We have identified a total of 214 hypermethylated and 142 hypomethylated regions in the 10 kb upstream region of transcription start site in pups of B12-deficient mothers, which are enriched in genes involved in fatty acid metabolism and mitochondrial transport/metabolism. B12 rehabilitation at conception and parturition is responsible for reversal of methylation status of many of these regions to control levels suggesting a causal association with metabolic phenotypes. Thus, maternal B12 restriction alters DNA methylation of genes involved in important metabolic processes and influences the offspring phenotype, which is reversed by B12 rehabilitation of mothers at conception.

中文翻译：

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大鼠母体维生素B12缺乏会改变其子代中代谢重要基因的DNA甲基化。

维生素B12缺乏症是世界范围内的关键问题，这种维生素的围孕期缺乏症与复杂的心血管疾病相关。在这些发育阶段的营养紊乱可能导致胎儿表观基因组发生变化。使用Wistar大鼠模型系统，我们更早地表明，母亲B12水平低与后代体重低，肥胖，胰岛素抵抗和后代甘油三酯水平升高有关，这可能使它们易患成年期心血管疾病。在这项研究中，我们调查了母体B12缺乏对后代全基因组DNA甲基化谱图的影响，以及母亲受孕时B12康复的影响。我们对四只Wistar大鼠的幼崽进行了肝脏肝脏的甲基化DNA免疫沉淀测序：对照（C），B12限制性（B12R），B12妊娠时恢复（B12RC）和B12分娩时恢复（B12RP）。与对照相比，我们已经分析了三组之间的差异甲基化标记。我们已经在B12缺陷型母亲的幼仔的转录起始位点的10 kb上游区域中鉴定出总共214个高甲基化和142个低甲基化区域，这些幼犬富含脂肪酸代谢和线粒体运输/代谢相关的基因。B12在受孕和分娩时的恢复负责将许多这些区域的甲基化状态逆转至控制水平，表明与代谢表型之间存在因果关系。从而，