Folate deficiency impairs decidualization and alters methylation patterns of the genome in mice
Folate deficiency impairs decidualization and alters methylation patterns of the genome in mice
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叶酸缺乏会损害小鼠的蜕膜化并改变基因组的甲基化模式
DOI：
10.1093/molehr/gav045
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发表时间：
2015-11-01
影响因子：
4
通讯作者：
He, Junlin
中科院分区：
文献类型：
--
作者：
Geng, Yanqing;Gao, Rufei;He, Junlin
现有证据表明不良妊娠结局与饮食因素密切相关。以往的研究主要集中在小鼠叶酸缺乏对胚胎发育的危害，而低叶酸水平对孕早期母体宫内环境的影响尚不清楚。由于我们先前的研究发现，FD治疗小鼠不会导致胚胎植入的明显缺陷，但伴有雌性生育力低下，我们接下来选择研究FD对植入后分子事件的潜在作用。我们观察到，蜕膜隆起在妊娠第6天开始发育不良。体内外功能实验结果表明，FD可抑制子宫内膜蜕膜化过程。DNA甲基化参与蜕膜化过程，叶酸作为甲基供体可以改变基因的甲基化模式。因此，我们假设FD通过改变相关基因的甲基化谱来损害母体子宫内膜的蜕膜化。采用还原型亚硫酸氢盐测序法检测小鼠妊娠第6-8天子宫内膜的甲基化水平。结果证实FD改变了基因组的甲基化模式，GO分析差异甲基化区域发现相关基因主要参与生物粘附、生物调节、细胞增殖、发育、代谢和信号传导等过程。此外，我们还发现了一些蜕膜转化调节因子的候选者，如Nr 1h 3和Nr 5a 1。这些数据表明，FD抑制蜕膜化，可能是通过改变小鼠基因组的甲基化模式。
Existing evidence suggests that adverse pregnancy outcomes are closely related with dietary factors. Previous studies in mice have focused on the harm of folate deficiency (FD) on development of embryo, while the effect of low maternal folate levels on maternal intrauterine environment during early pregnancy remains unclear. Since our previous study found that FD treatment of mice causes no apparent defects in embryo implantation but is accompanied by female subfertility, we next chose to investigate a potential role of FD on molecular events after implantation. We observed that the decidual bulges began to be stunted on pregnancy day 6. The results of functional experiments in vivo and in vitro showed that FD inhibited the process of endometrial decidualization. It has been confirmed that DNA methylation participates in decidualization, and folate as a methyl donor could change the methylation patterns of genes. Thus, we hypothesized that FD impairs maternal endometrial decidualization by altering the methylation profiles of related genes. Reduced representation bisulphite sequencing was carried out to detect the methylation profiles of endometrium on pregnancy day 6-8, which is equivalent to the decidualization period in mice. The results confirmed that FD changes the methylation patterns of genome, and GO analysis of the differentially methylated regions revealed that the associated genes mainly participate in biological adhesion, biological regulation, cell proliferation, development, metabolism and signalling. In addition, we found some candidates for regulators of decidual transformation, such as Nr1h3 and Nr5a1. The data indicate that FD inhibits decidualization, possibly by altering methylation patterns of the genome in mice.