Impact of maternal diet on the epigenome and potentially modifiable effects on offspring health

我们早年的经历可能会对我们的健康和幸福产生终生影响。例如，在西非冈比亚的一个农村人口中，我们观察到，在雨季出生的儿童在15至65岁之间死亡的可能性是那些出生在旱季的儿童的6倍。事实上，越来越多的证据表明，对终身健康的有害影响可以追溯到胚胎发育的早期阶段。这突显了研究潜在机制的重要性，以便能够理解并有望纠正将环境暴露与负面结果联系起来的过程。其中一个可能的机制涉及一种称为甲基化的过程，这是基因组的一种表观遗传修饰。甲基化需要一套确定的营养素，包括叶酸和维生素B，以提供必要的化合物，即所谓的甲基团，并进行必要的代谢转化。动物实验之前已经表明，在雌性小鼠怀孕前补充这些营养物质对它们的后代的外表有深远的影响(例如改变它们的毛色)，并且这些变化与它们DNA上更高水平的甲基化有关。到目前为止，还不知道人类是否会对后代产生类似的影响，但我们的团队最近提出了第一个人类存在的证据。自那以后，我们通过观察整个基因组的甲基化模式来跟进这项工作。我们在某些类型的基因中发现了与母体营养状况和受孕季节相关的异常甲基化模式的证据，特别是在一个基因(VTRNA2-1)中，该基因的甲基化中断以前与某些形式的癌症有关，也与免疫系统的负面影响有关。通过这笔拨款，我们希望以多种方式扩展这项工作。首先，我们希望通过观察更多的婴儿，使用更先进的技术以高分辨率询问表观基因组的关键区域，并全年寻找甲基化影响，来更准确地描述这些干扰模式。我们希望这将为表观基因组破坏的机制提供进一步的线索。其次，我们想要研究VTRNA2-1中甲基化中断的影响。我们的冈比亚研究中心是一个特别好的地方，因为我们能够将个人的表观遗传学信息与医疗记录和其他人口统计数据联系起来，我们还可以对已知甲基化异常的个人的血细胞进行详细的实验室调查。这些功能研究是将表观遗传效应与人类真实的、不利的健康后果联系起来的链的重要组成部分。最后，在先进的计算机建模的帮助下，我们将确定可能导致观察到的甲基化中断模式的MD相关营养物质的特定组合。然后，我们将开发一种营养补充剂来纠正观察到的次优营养状况，并将在随机对照试验中测试其有效性。如果有效，在未来的工作中，我们将寻求评估给准妈妈服用这种补充剂对后代甲基化的影响。人们希望，之前在一年中的特定时间怀孕的婴儿中观察到的甲基化中断模式将被防止。从长远来看，我们希望这里描述的工作将为母亲孕前补充战略提供参考，这些战略将直接导致改善婴儿生长和发育的结果，并为健康和福祉带来终身好处。

Our experiences in early life can have life-long effects on our health and wellbeing. For example, in a rural population in The Gambia in West Africa we have observed that children born in the rainy season are 6 times more likely to die between the ages of 15 and 65 than those born in the dry season. In fact there is mounting evidence that detrimental influences on lifelong health can stretch right back to the early stages of embryonic development. This underlines the importance of research into the underlying mechanisms, so that the processes linking environmental exposures to negative outcomes can be understood, and hopefully corrected.One such possible mechanism involves a process known as methylation, which is one type of 'epigenetic' modification of the genome. Methylation requires a defined set of nutrients including folic acid and B-vitamins, both to provide the necessary chemical compounds, known as methyl groups, and to undertake the necessary metabolic conversions. Animal experiments have previously shown that supplementing the diets of female mice with these nutrients before they conceive has a profound effect on their offspring's appearance (e.g. changing their coat colour) and that these changes were associated with higher levels of methylation on their DNA. Until now it was unknown whether similar effects on offspring methylation occur in humans, but our group recently presented first-in-human evidence that they do. We have since followed up this work by looking at patterns of methylation across the genome. We found evidence of unusual or 'disrupted' methylation patterns associated with both maternal nutrient status and season of conception in certain types of genes, and notably in one gene (VTRNA2-1), where disrupted methylation has previously been linked with some forms of cancer and also with negative effects on the immune system.With this grant we hope to extend this work in a number of ways. Firstly, we want to characterise these patterns of disruption more precisely by looking at a larger number of infants; interrogating key regions of the epigenome at high resolution using more advanced technologies; and looking for methylation effects all the year round. We hope this will provide further clues about the mechanisms underlying epigenomic disruption. Secondly, we want to investigate the effects of disrupted methylation in VTRNA2-1. Our Gambian research centre is a particularly good place to do this as we are able to link an individual's epigenetic information with medical records and other demographic data, and we can also conduct detailed laboratory investigations on blood cells in individuals known to have abberant methylation. These functional studies are an important part of the chain linking epigenetic effects to real, adverse health outcomes in people. Finally, with the help of advanced computer modelling, we will identify the specific combination of MD-related nutrients that may be causing the observed patterns of disrupted methylation. We will then develop a nutritional supplement to correct the observed suboptimal nutrient profile, and we will test its effectiveness in a randomised controlled trial. If effective, in future work we would seek to assess the effect on offspring methylation of giving this supplement to mothers-to-be. The hope is that the patterns of disrupted methylation previously observed in infants conceived at certain times of the year would then be prevented. In the longer term, we hope that the work described here will inform strategies for pre-conceptional supplementation in mothers that will lead directly to improved outcomes for infant growth and development, with life-long benefits for health and wellbeing.