Yan Weili, Zhang Yi, Wang Liping, Yang Wenhong, Li Chunying, Wang Liling, Gu Ping, Xia Yingqian, Yan Juhua, Shen Ying, Zhao Qian, Niu Dayan, Mu Kai, Jiang Yuan
1Department of Clinical Epidemiology, Children's Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102 China.
2Maternity and Child Health Center, International Peace Maternity & Child Health Hospital of China Welfare Institute, 910 Hengshan Road, Shanghai, 200030 China.
Genes Nutr. 2019 May 9;14:17. doi: 10.1186/s12263-019-0634-x. eCollection 2019.
Studies have shown that the effects of maternal nutrition exposure during gestation influence metabolic risk in early life through an epigenetic mechanism. Low glycaemic index (GI) diets benefit both maternal and neonatal gestational outcomes. We hypothesize that maternal dietary GI or glycaemic load (GL) changes during pregnancy impact placental DNA methylation, especially in insulin resistance-related genes.
From a clinical trial of overweight pregnant women, 12 subjects who successfully reduced their GI and another 12 whose GI increased despite the intervention were selected. A genome-wide differential methylation analysis of placental tissue DNA was conducted, followed by bioinformatic annotation and validation analysis. The distribution of genome-wide differentially methylated regions (DMRs) and CpG sites was described. Six CpG sites in regulatory regions of four insulin-related genes (, , , and ) were selectively validated by pyrosequencing. Pairwise Spearman correlation analysis was performed to test methylation-phenotype association in an additional 153 subjects from the same trial. Correlation between methylation of significant sites and placental mRNA expression of was also analysed.
Dietary GI decreased by 24.3 (26.2-20.1) in the group who responded appropriately to the intervention and increased by 19.6 (15.2-29.1) in the comparison group. Epigenome-wide analysis identified 108 DMRs and 365 CpG sites with < 0.05 adjusted by false discovery rate, distributed over all chromosomes. The methylation level of cg05009389 in the 3' UTR of was negatively correlated with maternal weight gain ( = - 0.21, = 0.027) and increase in insulin levels ( = - 0.24, = 0.015) during gestation. Methylation levels of cg17586860 and cg18197392 in the 5' UTR region of were negatively correlated with changes in dietary carbohydrate intake ( = - 0.24, s ≤ 0.006) and GL across gestation ( = - 0.23, s ≤ .008). This correlation survived the adjustment for maternal factors such as dietary GI, body mass index, and gestational diabetes. Up to 89% of cg18197392 methylation was explained by GL change. Cg14631053 methylation correlated positively with mRNA expression of in the placenta ( = 0.20, = 0.037)
We provide the first evidence that maternal dietary GI changes during gestation may impact placental DNA methylation of insulin regulation genes. This supports the hypothesis that placental methylation may be the epigenetic mechanism through which maternal diet influences the metabolic health of offspring.
研究表明，孕期母体营养暴露的影响通过表观遗传机制影响生命早期的代谢风险。低血糖指数（GI）饮食对母体和新生儿的妊娠结局均有益。我们假设孕期母体饮食GI或血糖负荷（GL）的变化会影响胎盘DNA甲基化，尤其是在胰岛素抵抗相关基因中。
从一项超重孕妇的临床试验中，选择了12名成功降低其GI的受试者和另外12名尽管进行了干预但其GI仍升高的受试者。对胎盘组织DNA进行全基因组差异甲基化分析，随后进行生物信息学注释和验证分析。描述了全基因组差异甲基化区域（DMR）和CpG位点的分布。通过焦磷酸测序选择性验证了四个胰岛素相关基因（、、和）调控区域中的六个CpG位点。对来自同一试验的另外153名受试者进行成对Spearman相关性分析，以测试甲基化与表型的关联。还分析了显著位点的甲基化与胎盘mRNA表达之间的相关性。
在对干预有适当反应 的组中，饮食GI下降了24.3（26.2 - 20.1），而在对照组中升高了19.6（15.2 - 29.1）。全表观基因组分析确定了108个DMR和365个CpG位点，经错误发现率调整后P<0.05，分布在所有染色体上。基因3'UTR中cg05009389的甲基化水平与孕期母体体重增加（r = - 0.21，P = 0.027）和胰岛素水平升高（r = - 0.24，P = 0.015）呈负相关。基因5'UTR区域中cg17586860和cg18197392的甲基化水平与孕期饮食碳水化合物摄入量的变化（r = - 0.24，P≤0.006）和GL的变化（r = - 0.23，P≤0.008）呈负相关。在对母体因素如饮食GI、体重指数和妊娠期糖尿病进行调整后，这种相关性仍然存在。高达89%的cg18197392甲基化可由GL变化解释。Cg14631053甲基化与胎盘中基因的mRNA表达呈正相关（r = 0.20，P = 0.037）
我们提供了首个证据，表明孕期母体饮食GI的变化可能会影响胰岛素调节基因的胎盘DNA甲基化。这支持了胎盘甲基化可能是母体饮食影响后代代谢健康的表观遗传机制这一假设。
