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.

中文翻译：

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在人类早期胚胎中建立环境敏感的 DNA 甲基化状态。

目前尚不清楚导致后来疾病的发育起源的分子机制。我们之前证明，女性围孕期营养可以预测其后代亚稳态表观等位基因 (ME) 的 DNA 甲基化。我们提出了一种全基因组筛选，产生 687 个 ME，并跟踪它们在人类体外受精胚胎的九个发育阶段的轨迹。ME 在着床-原肠胚形成过程中表现出极不寻常的甲基化动态，产生大量过量的中间甲基化状态，这表明响应外部信号的差异编程的潜力。通过在冈比亚农村进行的自然实验，我们发现对受孕季节敏感的基因组区域的 ME 高度富集，并表现出类似的非典型甲基化模式。ME 富含近端增强子和转录起始位点，并受基因型影响。总之，这些观察结果将 ME 定位为早期胚胎中编程的独特表观基因组特征，对遗传和围孕环境敏感，并具有影响表型的潜力。