Understanding early envirnomental influences on human epigenetic programmes

先前的工作主要集中在鉴定甲基化状态在个体之间存在差异的位点，但在个体内显示出强烈的跨组织相关性，这表明甲基化标记是在前胚中建立的。这些区域被认为对孕产期环境敏感——基于冈比亚队列的季节性——富含亚稳态外显子和亲本起源甲基化区域，其中许多标记了仅在胎盘中的印迹位点。为了了解这些环境敏感的甲基化热点的变异机制，解剖我们的模型组织中不同细胞的甲基化谱至关重要；胎盘。该项目将涉及在冈比亚连续旱雨季节收集的胎盘样本中生成全球表达和甲基化谱，并将结果与产前暴露相关联。一旦确定，与个体甲基化差异相关的营养暴露将使用胎盘类器官系统进行建模。

Previous work has focused on identifying loci whose methylation state varies between individuals but shows strong cross-tissue correlation within individuals, suggestive that the methylation marks were established in the pregastrulation embryo. These regions, recognised as sensitive to periconceptional environment- based on seasonality in Gambian cohorts- are enriched for metastable epialleles and regions of parent-of-origin methylation, many of which demark imprinted loci solely in the placenta. In order to understand the mechanisms involved in variation at these environmentally sensitive methylation hotspots, it is crucial to dissect the methylation profiles of different cells within our model tissue; the placenta. The project will involve generating global expression and methylation profiles in placenta samples from the Gambia collected across consecutive rainy-dry seasons and correlating outcomes with prenatal exposures. Once established, nutrition exposures associated with between individual methylation differences will be modelled using a placenta organoid system.