Nutrition and the epigenome: early environmental factors influencing human developmental programming

我们身体中的每个细胞都包含从父母那里继承的相同DNA蓝图（除了精子和卵子包含半个副本）。这些基因的解码和表达需要精细调控，以产生不同的细胞类型并控制细胞代谢。这是通过对DNA的“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甲基标记基因组的某些区域来实现的，这些甲基往往会阻止基因表达。每次细胞分裂时，大部分DNA甲基化都会被忠实地遗传下来，因此成为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头几天内基本上被清除，并为胚胎创造了一个新的“甲基化组”。我们研究了冈比亚农村的一个季节性自然实验，在这个实验中，概念发生在非常不同的饮食和营养条件下。我们已经证明，基因组中某些“环境敏感热点”对婴儿的受孕季节非常敏感。这些热点具有特征性的签名，表明它们在非常早期的胚胎中被永久改变。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，并调整发育中的胎儿以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中的某些可能与肥胖、癌症和甲状腺疾病等疾病有关。在这项资助中，我们试图更好地了解饮食如何影响这些甲基化标记的形成，甲基化组的哪些区域对这种影响特别敏感，它们如何影响胎盘和胎儿的发育，以及最终这些变化对婴儿的发育和终生健康有何影响。为了实现这一目标，我们将跟踪冈比亚农村计划怀孕的家庭，并在+/-15天的概念，以更好地解释驱动我们研究的表观遗传变化的环境因素。我们将使用先进的代谢组学方法来测量DNA甲基化所需途径的差异，并寻找饮食以外的可能因素（包括农药和其他有毒物质暴露，药物等）。我们还将寻找母亲肠道微生物组的季节性差异，看看这是否会影响我们所看到的变化。我们将使用新的精细靶向表观遗传阵列来研究我们感兴趣的热点，并了解它们是如何以及为什么进化的，特别关注这些变化如何影响基因组过程最后，我们将研究这些变化对新出生的婴儿的影响，并在未来跟踪这些变化。这将为全世界的研究人员创造一个开放的、可访问的“早期发育表观遗传生物资源”。

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 methyl groups 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.In this grant, we seek to better understand HOW diet affects the laying down of these methylation marks, WHICH areas of the methylome are especially sensitive to such influences, HOW they influence the development of the placenta and fetus, and ultimately WHAT effects these changes have on the baby's development and life-long health.To achieve this, we will follow rural Gambian families planning to conceive and collect data and blood samples within +/-15 days of conception to much better characterise the environmental factors that are driving the epigenetic changes we study. We will use advanced metabolomic methods to measure differences in the pathways required for DNA methylation and search for possible factors beyond diet (including pesticide and other toxic exposures, pharmaceuticals, etc). We will also search for seasonal differences in the mothers' gut microbiome to see if that may be influencing the changes we see.We will use new finely-targeted epigenetic arrays to study our hotspots of interest and learn how and why they might have evolved, playing special attention to how these changes affect genomic processes (such as imprinting) that are crucial for placental (and hence fetal) development.Finally we will examine the effects of these changes on the babies born in the new cohort and follow them into the future. This will create an open, accessible 'Early Developmental Epigenetic BioResource' for researchers worldwide.