Nutrition-sensitive epigenetic mechanisms in the early human embryo - developing insights from stem cell and organoid models

我们体内的每个细胞都含有从父母那里遗传来的一模一样的DNA蓝图（精子和卵子除外，它们只含有半个副本）。这些基因的解码和表达需要被精细地调节，以产生不同的细胞类型和控制细胞代谢。这是通过对DNA进行“表观遗传”修饰来实现的。表观遗传调控的一种形式是通过用化学“甲基”标签标记基因组的某些区域来实现的，这种标记往往会阻止基因表达。每次细胞分裂时，大部分DNA甲基化都忠实地遗传下来，因此充当了基因运作的半永久性调节器。当精子与卵子受精时，每个卵子上的甲基化标记在受孕后的最初几天内大部分被抹去，一个新的“甲基组”为胚胎产生。我们研究了冈比亚农村自然的季节性实验，在这个实验中，不同的饮食和营养条件下会产生不同的观念。我们已经证明，基因组中的某些“环境敏感热点”对婴儿的受孕季节非常敏感。这些热点有一个特征，表明它们在胚胎早期就被永久改变了。我们相信它们可能已经进化到感知母亲的（营养）环境，记录这些信息，并使发育中的胎儿适应最适合预测的未来条件。如果未来的条件不同，这些变化可能变得不适应并导致疾病。我们已经证明，这些可变区域中的某些可能与肥胖、癌症和甲状腺疾病等疾病有关。我们的冈比亚自然实验为早期人类胚胎中发生的环境敏感分子过程提供了重要线索。然而，为了充分了解这些过程并确认特定的营养作用，我们需要在胚胎细胞和相关结构中测试我们的发现。这个奖项让我有机会在剑桥大学的遗传学系呆上一段时间。这个小组在研究早期胚胎的分子过程方面处于领先地位，因此他们是指导我开展前沿实验的理想宿主，这些实验需要将冈比亚营养表观遗传学研究带入下一个阶段。

Each cell in our body contains an identical DNA blueprint inherited from our parents (excepting sperm and eggs that contain half a copy). The decoding and expression of these genes needs to be finely regulated to make different cell types and govern cell metabolism. This is achieved by 'epigenetic' modifications to the DNA. One form of epigenetic regulation is achieved by marking certain regions of the genome with chemical 'methyl group' tags that tend to block gene expression. Most of this DNA methylation is faithfully inherited every time cells divide and so acts as a semi-permanent regulator of how genes operate.When sperm fertilises egg the methylation marks on each are largely erased in the first few days after conception and a new 'methylome' is created for the embryo. We have studied a seasonal experiment of nature in rural Gambia whereby conceptions occur against very different dietary and nutritional conditions. We have shown that certain 'environmentally- sensitive hotspots' across the genome are very sensitive to the baby's season of conception. These hotspots have a characteristic signature indicating that they are permanently altered in the very early embryo. We believe that they may have evolved to SENSE the mother's (nutritional) environment, RECORD that information, and ADAPT the developing fetus to be best suited to the predicted future conditions. If the future conditions are different these changes may become maladaptive and cause disease. We have already shown that certain of these variable regions may be linked to diseases such as obesity, cancer and thyroid disease.Our Gambian natural experiment has provided vital clues about environmentally sensitive molecular processes occurring in the early human embryo. However, in order to fully understand these processes and to confirm specific nutrient effects, we need to test our discoveries in embryonic cells and associated structures. This award would allow me to spend time in the Department of Genetics at the University of Cambridge. This group has pioneered work investigating molecular processes in the early embryo and they therefore make ideal hosts to guide me in developing the cutting edge experiments that are required to take our Gambian nutritional epigenetics research to the next stage.