Medical Research Council Unit The Gambia at the London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
U.S. Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Departments of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Sci Adv. 2018 Jul 11;4(7):eaat2624. doi: 10.1126/sciadv.aat2624. eCollection 2018 Jul.
The molecular mechanisms responsible for the developmental origins of later disease are currently unknown. We previously demonstrated that women's periconceptional nutrition predicts their offspring's DNA methylation at metastable epialleles (MEs). We present a genome-wide screen yielding 687 MEs and track their trajectories across nine developmental stages in human in vitro fertilization embryos. MEs exhibit highly unusual methylation dynamics across the implantation-gastrulation transition, producing a large excess of intermediate methylation states, suggesting the potential for differential programming in response to external signals. Using a natural experiment in rural Gambia, we show that genomic regions sensitive to season of conception are highly enriched for MEs and show similar atypical methylation patterns. MEs are enriched for proximal enhancers and transcription start sites and are influenced by genotype. Together, these observations position MEs as distinctive epigenomic features programmed in the early embryo, sensitive to genetic and periconceptional environment, and with the potential to influence phenotype.
导致后期疾病发生的发育起源的分子机制目前尚不清楚。我们之前的研究表明，女性的围孕期营养状况可以预测其后代在不稳定的表观等位基因（MEs）上的 DNA 甲基化。我们进行了一项全基因组筛查，得到了 687 个 MEs，并在人类体外受精胚胎的九个发育阶段中追踪了它们的轨迹。MEs 在着床-原肠胚形成过渡过程中表现出非常不寻常的甲基化动态，产生了大量中间甲基化状态，这表明它们可能对外部信号有不同的编程反应。利用冈比亚农村的一项自然实验，我们发现，对受孕季节敏感的基因组区域高度富集 MEs，并表现出类似的非典型甲基化模式。MEs 富含近端增强子和转录起始位点，并受基因型影响。综上所述，这些观察结果将 MEs 定位为早期胚胎中编程的独特表观基因组特征，对遗传和围孕期环境敏感，并有可能影响表型。
