Obesity and deregulation of imprinted genes in early life

描述(申请人提供)：随着发达国家儿童肥胖率的上升，肥胖症的病因学研究集中在遗传变异和可改变的风险因素之间的相互作用，这些因素包括能量平衡，估计为卡路里摄入量减去卡路里消耗。另一种令人信服的解释是，环境诱导的表观遗传机制的放松，引导参与能量平衡的基因表达，可能最终导致基因表达谱易患肥胖症。由于印记基因受表观遗传机制的调控，而且它们通常只在一个亲本染色体上表达，它们特别容易受到遗传和/或表观遗传去调控的影响。事实上，父系表达的生长因子IGF2的印迹调控元件上的DNA甲基化异常与肥胖和过度生长障碍的风险增加有关。肥胖人群循环中DLK1水平升高，DLK1和NNAT均参与脂肪形成。通过破坏印迹基因GNasx1，建立了小鼠肥胖模型。与印记放松管制相关的机制直到现在才被解开。在怀孕期间喂给雌性小鼠丰富的甲基供体饮食会触发幼鼠Agti基因甲基化的改变，这随后调节了肥胖和糖尿病的风险。在怀孕期间吸烟的母亲所生的儿童中，持续性儿童肥胖的倾向更高，我们的数据支持IGF2在吸烟母亲所生的新生儿中发生表观遗传改变和上调。我们的中心假设是，早期暴露增加了印记基因调控元件表观遗传去调控的风险，导致生长调控基因的表达改变，随后后代体重迅速增加，助长了儿童肥胖症的流行。我们的目标是：(1)确定控制出生时12个印迹基因的印迹基因调节区的甲基化是否与1岁、3岁和5岁儿童体重迅速增加和肥胖的风险增加相关；(2)确定子宫内暴露于母体甲基供体丰富的饮食和/或吸烟是否与这些年龄段儿童印迹基因调控区DNA异常甲基化的风险增加和肥胖风险增加相关；(3)确定儿童的饮食(3岁和5岁)是否与这些印迹调控元素的甲基化谱的变化有关。还将在1岁和5岁时生成约14,500个基因的全基因组甲基化图谱，以评估甲基化在快速生长和肥胖中的作用。在我们的新生儿表观遗传学研究(Nest)中，我们将跟踪690名参与者，评估饮食，收集人体测量数据和口腔细胞。我们将把Nest的孕周、产前、分娩和一岁的数据与建议收集的3岁和5岁的数据结合起来，以评估这些暴露与印记调节元素的表观遗传学变化和肥胖的关系。理解表观遗传学在儿童肥胖发生中的作用将最终导致预防肥胖和相关人类疾病的新方法。 公共卫生相关性： 公共卫生声明相关这一纵向流行病学项目将研究产前和儿童早期营养如何影响据信在肥胖和肥胖相关慢性疾病的发展中发挥作用的基因的功能。由于营养相关的基因解除调控模式可能是可逆的，识别与基因功能异常相关的营养和其他风险因素可能会导致针对儿童肥胖症和成人发病的肥胖相关慢性病的治疗和公共卫生干预。

DESCRIPTION (provided by applicant): As childhood obesity prevalence escalates in developed countries, etiologic studies of obesity have focused on the interaction between genetic variants and modifiable risk factors that encompass energy balance, estimated as caloric intake less caloric expenditure. A compelling alternative explanation is that environmentally induced deregulation of epigenetic mechanisms that guide expression of genes involved in energy balance may culminate in gene expression profiles that predispose to an obese phenotype. Because imprinted genes are regulated by epigenetic mechanisms, and because they are normally expressed from only one parental chromosome, they are particularly susceptible to genetic and/or epigenetic deregulation. Indeed, aberrant DNA methylation at imprint regulatory elements of the paternally expressed growth factor, IGF2, have been associ- ated with increased risk of obesity and overgrowth disorders. DLK1 is elevated in the circulation of obese hu- mans, and both DLK1 and NNAT are involved in adipogenesis. An obesity model in mice was generated through disruption of imprinted Gnasxl. Mechanisms associated with imprint deregulation are only now being unraveled. Feeding female mice a methyl group donor-rich diet during pregnancy triggers altered methylation of the Agouti locus in pups, which subsequently modulates risk of obesity and diabetes. There is a higher pro- pensity for persistent childhood obesity in children born to mothers who smoke during pregnancy, and our data support that IGF2 is epigenetically altered and upregulated in neonates born to smoking mothers. Our central hypothesis is that early exposures increase the risk of epigenetic deregulation of imprinted gene regulatory elements, resulting in altered expression of growth regulatory genes and subsequent rapid weight gain in the offspring, fueling the childhood obesity epidemic. Our aims are to: (1) Determine if altered methylation of im- printed gene regulatory regions controlling 12 imprinted genes at birth is associated with increased risk of rapid weight gain and obesity in children at age 1, 3 and at 5 years; (2) Determine if in utero exposures to a maternal methyl group donor-rich diet and/or cigarette smoke is associated with increased risk of aberrant DNA methyla- tion at imprinted gene regulatory regions and risk of obesity in children at these ages; (3) Determine if the child's diet (ages 3 and 5 years) is associated with alterations in methylation profiles at these imprint regulatory elements. Genome-wide methylation profiles for ~14,500 genes will also be generated at ages 1 and 5 years to assess the role of methylation in rapid growth and obesity. We will follow 690 participants in our Newborn Epigenetics STudy (NEST) and assess diet, collect anthropometric measurements and buccal cells. We will combine NEST periconceptional, prenatal, parturition and age one year data with data proposed for collection at ages 3 and 5 years to evaluate these exposures in relation to epigenetic changes at imprint regu- latory elements and obesity. Understanding the role of epigenetics in the genesis of childhood obesity will ulti- mately lead to new ways of preventing obesity and associated human diseases. PUBLIC HEALTH RELEVANCE: Public Health Statement of Relevance This longitudinal epidemiology project will study how prenatal and early childhood nutrition affect the function of genes believed to play role in the development of obesity and obesity-related chronic disease. Because nutrition-related patterns of gene deregulation are potentially reversible, identifying nutritional and other risk factors associated with abnormal gene functioning may lead to therapeutic and public health interventions for childhood obesity and for adult onset, obesity-related chronic diseases.