Epigenetic events in micronutrient programming during early development

早期发育过程中微量营养素编程的表观遗传事件

• 批准号: BB/F02293X/1
• 负责人: David Dunger
• 金额: $ 68.83万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FF02293X%2F1
• 关键词: Epigenetic; events; micronutrient; programming; during

Although the information content of the DNA is determined primarily by its nucleotide sequence, further modifications of the DNA itself or the proteins binding to it are important to determine which genes are turned on and off. These modifications are influenced by environmental factors. One of them, methylation of the DNA molecule is dependent on the supply and metabolism of several vitamins and trace elements, such as folic acid, vitamins B6 and B12 and zinc. If pregnant mice are given food deficient in these factors, DNA methylation in the offspring is altered with resultant changes in gene regulation. A similar mechanism is possible in humans and could account for permanent consequences of micronutrient (that is, vitamin and trace element) deficiencies, however, data supporting this hyposthesis are lacking. Our aim is to study whether the micronutrient supply of the pregnant mother during early human embryonic development influences DNA methylation in the offspring. Of particular interest is the DNA methylation of genes which could potentially effect growth and development of the embryo and placenta. We will take advantage of an ongoing trial run by the MRC Keneba Field Station in the Gambia. This is a double blind, randomised control trial food supplementation containing multiple micronutrients given to women of childbearing age living in rural Gambia. The major endpoints of the study are fetal growth, placental development, weight, length and head circumference of the newborn infant. We will study DNA from children whose mothers received micronutrient supplementation and from those whose mothers received placebo only. Using this design we will study whether micronutrients supplementation has an effect on total methylation of the genome using a simple biochemical assay. We will also use methods that assess methylation at large numbers of specific points throughout the human DNA at the sametime in order to identify genes which are methylated in one group of subjects but not in the other group. The latter method includes the use of microarray (DNA chip) technology that allows for genome-wide methylation analysis in one experiment. We will also investigate DNA methylation of individual 'imprinted' genes. These are particularly interesting candidates for epigenetic modulation as any one of the two copies, either the maternal or the paternal switched on and this is mainly regulated by DNA methylation of sequences called 'imprinting centres'. We will investigate and compare DNA methylation of 9 imprinting centres controlling 8 groups of such imprinted genes. Many of these genes are thought to be important in the control of growth of the unborn child. We will, therefore, assess whether DNA methylation of these 'imprinting centres' is different in individuals with or without maternal micronutrient supplementation. If the trial shows that micronutrient supplementation does indeed improve the growth of the fetus, the weight of the placenta, the size of the newborn then our data could provide supportive evidence that this may be related to altered methylation of these imprinted genes. Evidence in humans that periconceptual variation in nutrients can result in permanent epigenetic changes would have profound effects on the direction of future human developmental biology. It would initiate follow up studies to investigate the consequence of such changes in terms of gene function and could open up new avenues for drug development. For health care professionals and the general public, it would lead to more detailed examination of the importance of maternal diet both before and during pregancy.

虽然DNA的信息内容主要由其核苷酸序列决定，但DNA本身或与其结合的蛋白质的进一步修饰对于确定哪些基因被打开和关闭是重要的。这些变化受环境因素的影响。其中之一，DNA分子的甲基化依赖于几种维生素和微量元素的供应和代谢，如叶酸，维生素B6和B12以及锌。如果给怀孕的小鼠提供缺乏这些因子的食物，后代的DNA甲基化就会改变，从而导致基因调控的变化。类似的机制在人类中也是可能的，可以解释微量营养素（即维生素和微量元素）缺乏的永久性后果，但是，缺乏支持这一假设的数据。我们的目的是研究在早期人类胚胎发育过程中孕妇的微量营养素供应是否会影响后代的DNA甲基化。特别令人感兴趣的是可能影响胚胎和胎盘生长和发育的基因的DNA甲基化。我们将利用MRC Keneba野外站在冈比亚进行的试验。这是一项双盲、随机对照试验，向生活在冈比亚农村的育龄妇女提供含有多种微量营养素的食物补充剂。研究的主要终点是胎儿生长、胎盘发育、新生儿体重、身长和头围。我们将研究母亲接受微量营养素补充剂的儿童和母亲只接受安慰剂的儿童的DNA。使用这种设计，我们将研究微量营养素补充是否有一个使用简单的生化分析对基因组总甲基化的影响。我们还将使用同时评估人类DNA中大量特定点的甲基化的方法，以鉴定在一组受试者中甲基化而在另一组受试者中没有甲基化的基因。后一种方法包括使用微阵列（DNA芯片）技术，该技术允许在一个实验中进行全基因组甲基化分析。我们还将研究个别“印记”基因的DNA甲基化。这些是表观遗传调节的特别有趣的候选者，因为两个拷贝中的任何一个，无论是母本还是父本，都被打开，这主要是由称为“印记中心”的序列的DNA甲基化调节的。我们将调查和比较控制8组这样的印记基因的9个印记中心的DNA甲基化。许多这些基因被认为是重要的控制未出生的孩子的成长。因此，我们将评估这些“印记中心”的DNA甲基化是否在有或没有母体微量营养素补充的个体中是不同的。如果试验表明，微量营养素补充确实可以改善胎儿的生长，胎盘的重量，新生儿的大小，那么我们的数据可以提供支持性证据，这可能与这些印记基因的甲基化改变有关。在人类中的证据表明，营养物质的近概念变化可以导致永久性的表观遗传变化，这将对未来人类发育生物学的方向产生深远的影响。它将启动后续研究，以调查这种基因功能变化的后果，并可能为药物开发开辟新的途径。对于卫生保健专业人员和普通公众来说，这将导致更详细地检查孕妇怀孕前和怀孕期间饮食的重要性。

项目成果

Deletion of the Imprinted Phlda2 Gene Increases Placental Passive Permeability in the Mouse.

• DOI: 10.3390/genes12050639
• 发表时间: 2021-04-25
• 期刊: Genes
• 影响因子: 3.5
• 作者: Angiolini E;Sandovici I;Coan PM;Burton GJ;Sibley CP;Fowden AL;Constância M
• 通讯作者: Constância M

Associations between a fetal imprinted gene allele score and late pregnancy maternal glucose concentrations.

• DOI: 10.1016/j.diabet.2017.03.002
• 发表时间: 2017-09
• 期刊: Diabetes & metabolism
• 影响因子: 7.2
• 作者: Petry CJ;Mooslehner K;Prentice P;Hayes MG;Nodzenski M;Scholtens DM;Hughes IA;Acerini CL;Ong KK;Lowe WL Jr;Dunger DB
• 通讯作者: Dunger DB

Associations between a fetal imprinted gene allele score and late pregnancy maternal glucose concentrations

胎儿印记基因等位基因评分与妊娠晚期母体葡萄糖浓度之间的关联

• DOI: 10.17863/cam.10556
• 发表时间: 2017
• 作者: Petry C