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包含一个从父母那里遗传来的完全相同的DNA蓝图(除了精子和卵子，它们含有一半的副本)。这些基因的解码和表达需要进行精细调控，以形成不同的细胞类型，并控制细胞新陈代谢。这是通过对DNA进行“表观遗传”修改来实现的。一种形式的表观遗传调控是通过在基因组的某些区域标记化学“甲基”标签来实现的，这些标签往往会阻止基因的表达。每次细胞分裂时，大部分DNA甲基化都会被忠实地继承，因此对基因的运作起到了半永久性的调节作用。当精子受精时，卵子上的甲基化标记在受孕后的头几天基本上被抹去，一个新的甲基组就会为胚胎创造出来。我们研究了冈比亚农村的季节性自然实验，在这种实验中，受孕的人在非常不同的饮食和营养条件下受孕。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特征，表明它们在非常早期的胚胎中被永久改变。我们认为，它们可能已经进化到感知母亲的(营养)环境，记录信息，并使发育中的胎儿最适合预测的未来条件。如果未来的情况不同，这些变化可能会变得不适应并导致疾病。我们已经证明了这些可变区中的某些可能与肥胖、癌症和甲状腺疾病等疾病有关。我们冈比亚的自然实验为人类早期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效应，我们需要测试我们在胚胎细胞和相关结构中的发现。这一奖项将允许我在剑桥大学遗传学系度过一段时间。这个小组是研究早期胚胎分子过程的开创性工作，因此他们是指导我开发尖端实验的理想宿主，这些实验是将我们冈比亚的营养表观遗传学研究带入下一阶段所必需的。

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.