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

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用倾向于阻止基因表达的甲基标记基因组的某些区域来实现的。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。我们已经证明了某些可变区可能与肥胖、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，哪些甲基组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身健康有什么影响。为了实现这一点，我们将跟踪冈比亚农村家庭，计划在怀孕+/-15天内怀孕并收集数据和血液样本，以更好地表征推动我们研究的表观遗传学变化的环境因素。我们将使用先进的代谢组学方法来衡量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暴露、药物等)。我们还将寻找母亲肠道微生物组的季节差异，看看这是否会影响我们看到的变化。我们将使用新的精确定位的表观遗传阵列来研究我们感兴趣的热点，并了解它们可能如何以及为什么会进化，特别关注这些变化如何影响对胎盘(因此是胎儿)发育至关重要的基因组过程(例如印迹)。最后，我们将检查这些变化对新队列中出生的婴儿的影响，并在未来跟踪它们。这将为世界各地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.