Center for Pregnancy and Newborn Research, Department of Obstetrics and Gynecology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
Department of Computer Science, University of Texas at San Antonio, San Antonio, Texas, United States of America.
PLoS One. 2017 Oct 18;12(10):e0186115. doi: 10.1371/journal.pone.0186115. eCollection 2017.
The inflammatory and metabolic derangements of obesity in pregnant women generate an adverse intrauterine environment, increase pregnancy complications and adverse fetal outcomes and program the fetus for obesity and metabolic syndrome in later life. We hypothesized that epigenetic modifications in placenta including altered DNA methylation/hydroxymethylation may mediate these effects. Term placental villous tissue was collected following cesarean section from lean (prepregnancy BMI<25) or obese (BMI>30) women. Genomic DNA was isolated, methylated and hydroxymethylated DNA immunoprecipitated and hybridized to the NimbleGen 2.1M human DNA methylation array. Intermediate metabolites in placental tissues were measured by HPLC-ESI-MS, ascorbate levels by reverse phase HPLC and gene expression by RT-PCR. Differentially methylated and hydroxymethylated regions occurred across the genome, with a 21% increase in methylated but a 31% decrease in hydroxymethylated regions in obese vs lean groups. Whereas increased methylation and decreased methylation was evident around transcription start sites of multiple genes in the GH/CSH and PSG gene clusters on chromosomes 17 and 19 in other areas there was no relationship. Increased methylation was associated with decreased expression only for some genes in these clusters. Biological pathway analysis revealed the 262 genes which showed reciprocal differential methylation/ hydroxymethylation were enriched for pregnancy, immune response and cell adhesion-linked processes. We found a negative relationship for maternal BMI but a positive relationship for ascorbate with α-ketoglutarate a metabolite that regulates ten eleven translocase (TET) which mediates DNA methylation. We provide evidence for the obese maternal metabolic milieu being linked to an altered DNA methylome that may affect placental gene expression in relation to adverse outcomes.
孕妇肥胖引起的炎症和代谢紊乱会导致宫内环境不良，增加妊娠并发症和不良胎儿结局，并使胎儿在以后的生活中容易肥胖和患代谢综合征。我们假设胎盘的表观遗传修饰，包括改变的 DNA 甲基化/羟甲基化，可能介导这些效应。剖宫产术后从瘦（孕前 BMI<25）或肥胖（BMI>30）妇女收集胎盘绒毛组织。分离基因组 DNA，用甲基化和羟甲基化 DNA 免疫沉淀法处理，然后与 NimbleGen 2.1M 人类 DNA 甲基化芯片杂交。通过 HPLC-ESI-MS 测量胎盘组织中的中间代谢物，通过反相 HPLC 测量抗坏血酸水平，通过 RT-PCR 测量基因表达。差异甲基化和羟甲基化区域发生在整个基因组中，与瘦组相比，肥胖组的甲基化区域增加了 21%，而羟甲基化区域减少了 31%。虽然在 GH/CSH 和 PSG 基因簇的多个基因的转录起始位点周围可以看到增加的甲基化和减少的甲基化，但在其他区域没有这种关系。这些簇中只有一些基因的增加的甲基化与表达减少有关。生物途径分析显示，262 个表现出相反差异甲基化/羟甲基化的基因富集了妊娠、免疫反应和细胞黏附相关过程。我们发现，母体 BMI 与某些基因的表达呈负相关，但与 α-酮戊二酸呈正相关，α-酮戊二酸是一种调节 TET（介导 DNA 甲基化的酶）的代谢物。我们提供的证据表明，肥胖的母体代谢环境与改变的 DNA 甲基组有关，这可能会影响与不良结局相关的胎盘基因表达。
