Obesity and deregulation of imprinted genes in early life

早期生命中的肥胖和印记基因的失调

• 批准号: 8117085
• 负责人: Cathrine Hoyo
• 金额: $ 54.62万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-27 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8117085
• 关键词: Aberrant DNA Methylation; Adult; Affect; Age; Alleles; Animals; Barker Hypothesis; Birth; Blood Circulation; CDKN1C gene; Caloric Restriction; Cells; Central obesity; Child; Chromosomes; Chronic Disease; Collection; Coronary heart disease; DNA Methylation; DNA Sequence; Data; Developed Countries; Development; Diabetes Mellitus; Diet; Dietary Supplementation; Diploidy; Disease; Elements; Energy Intake; Environment; Environmental Risk Factor; Epidemic; Epidemiologic Studies; Epidemiology; Epigenetic Process; Etiology; Expenditure; Exposure to; Female; First Births; Folate; Gene Expression; Genes; Genetic; Genetic Transcription; Genome; Genomics; Growth; Growth Factor; H19 gene; Human; Hypermethylation; IGF2 gene; Individual; Infant; Inherited; Intervention; Lead; Life; Link; Measurement; Metabolism; Methylation; Modeling; Molecular; Molecular Profiling; Mothers; Mus; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Nucleic Acid Regulatory Sequences; Nutrient; Nutritional; Obesity; Obesity associated disease; Oncogene Deregulation; Overweight; PLAGL1 gene; Participant; Pattern; Perinatal; Perinatal Exposure; Phenotype; Physical activity; Play; Predisposition; Pregnancy; Prevalence; Public Health; RNA; Regulator Genes; Regulatory Element; Reliance; Reporting; Risk; Risk Factors; Role; Route; SNRPN; Site; Smoke; Smoking; Therapeutic; Umbilical Cord Blood; Weight Gain; Woman; aged; base; cigarette smoking; cigarette smoking; cohort; early childhood; energy balance; experience; feeding; gene function; genetic variant; genome-wide; human disease; imprint; in utero; lipid biosynthesis; methyl group; modifiable risk; neonate; nutrition; obesity in children; obesity risk; offspring; prenatal; prenatal exposure; prevent; public health relevance; pup; rapid growth; sex; uptake

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.

描述（由申请人提供）：随着发达国家的儿童肥胖症患病率升级，对肥胖症的病因学研究集中在遗传变异和涵盖能量平衡的可修改风险因素之间的相互作用，估计是热量摄入量减少热量的热量支出。一个令人信服的替代解释是，环境诱导的表观遗传机制的放松管制，指导参与能量平衡的基因的表达可能最终导致易于肥胖表型的基因表达谱。由于印迹基因受到表观遗传机制的调节，并且由于它们通常仅从一个父母的染色体中表达，因此它们特别容易受到遗传和/或表观遗传失调的影响。实际上，在父亲表达生长因子IGF2的烙印调节元件下，异常的DNA甲基化已与肥胖和过度生长疾病的风险增加相关。 DLK1在肥胖的Humans循环中升高，DLK1和NNAT都参与脂肪形成。小鼠中的肥胖模型是通过印迹GNASXL的破坏而产生的。与烙印放松管制相关的机制直到现在才被解开。在怀孕期间喂养雌性小鼠甲基供体饮食富含甲基的供体饮食改变了幼犬中阿古蒂基因座的甲基化，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持续的儿童肥胖症的持续性较高，我们的数据支持在吸烟母亲出生的新生儿表观上改变了IGF2。我们的核心假设是，早期暴露会增加对印迹基因调节元件的表观遗传放松管制的风险，从而导致生长调节基因的表达改变，并随后在后代的快速体重增加，从而加剧了儿童肥胖症的流行。我们的目的是：（1）确定控制12个印迹基因的印刷基因调节区域的甲基化是否与1、3岁和5岁儿童的快速体重增加和肥胖的风险增加有关； （2）确定在子宫内暴露于母体甲基供体饮食和/或香烟烟雾是否与在这些年龄段的儿童中造成的基因调节区域异常DNA甲基抗体的风险增加有关； （3）确定儿童的饮食（3岁和5岁）是否与这些烙印调节元素的甲基化谱改变有关。 〜14,500个基因的全基因组甲基化谱也将在1岁和5岁时产生，以评估甲基化在快速生长和肥胖中的作用。我们将关注我们的新生儿表观遗传学研究（NEST）的690名参与者，并评估饮食，收集人体测量和颊细胞。我们将结合巢周年感受，产前，分娩和年龄的数据，并提议在3岁和5岁时收集数据，以评估这些暴露于印记调节元素和肥胖症的表观遗传变化。了解表观遗传学在儿童肥胖起源中的作用最终会导致预防肥胖和相关人类疾病的新方法。 公共卫生相关性： 公共卫生的相关性声明这个纵向流行病学项目将研究产前和幼儿营养如何影响被认为在肥胖和肥胖相关慢性疾病的发展中起作用的基因的功能。由于与营养相关的基因失调模式可能是可逆的，因此鉴定与异常基因功能相关的营养和其他危险因素可能会导致儿童肥胖症的治疗和公共卫生干预措施以及与肥胖相关的成人发作，与肥胖相关的慢性疾病。