Characterizing the Human Imprint Regulatory Regions Associated with Childhood Obesity

表征与儿童肥胖相关的人类印记调节区域

• 批准号: 10011940
• 负责人: Cathrine Hoyo
• 金额: $ 63.51万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-06 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011940
• 关键词: 5 year old; Adolescent; Affect; Age; Aging; Algorithms; Alleles; Binding Sites; Bioinformatics; Biological Assay; Birth; Blood Cells; Brain; Cell Aging; Cell Differentiation process; Cells; Characteristics; Child; Childhood; Chromatin Structure; Conceptus; CpG Islands; CpG dinucleotide; Cues; Cytosine; DNA; DNA Methylation; Data; Databases; Deoxyribonucleases; Deposition; Desire for food; Development; Disease; Elements; Embryo; Embryonic Development; Endoderm; Environmental Exposure; Epigenetic Process; Etiology; Failure; Fatty acid glycerol esters; Female; Funding; Gene Cluster; Gene Expression; Generations; Genes; Genetic; Genetic Polymorphism; Genomic Imprinting; Germ Layers; Goals; Growth; Growth Disorders; Health; Human; Human Genome; Hypersensitivity; Individual; Kidney; Life; Life Cycle Stages; Link; Liver; Measurement; Measures; Mediating; Mesoderm; Metabolism; Methods; Methylation; Modification; Mutation; Non obese; Nucleic Acid Regulatory Sequences; Nutrient; Obesity; Oocytes; Outcome; Parents; Pathologic; Pathway interactions; Pattern; Peripheral; Population; Prevalence; Proxy; Records; Regulation; Risk Assessment; Role; Saliva; Sampling; Satiation; Screening procedure; Site; Somatic Cell; Specificity; Time; Tissues; Umbilical Cord Blood; base; bisulfite sequencing; cell type; cohort; deep sequencing; demethylation; early life exposure; epigenetic regulation; fetal; genetic variant; genome-wide; histone modification; imprint; interest; male; obesity development; obesity in children; obesity risk; promoter; prospective; response; screening; sex; sociodemographics; sperm cell; tool; transcription factor; whole genome

PROJECT SUMMARY/ABSTRACT The rapid increase in the prevalence of obesity in the last 30 years has led to the hypothesis that epigenetic mechanisms mediate associations between environmental cues and obesity outcomes. Nevertheless, epigenetic regions that alter obesity risk are still largely unknown. We presently lack a screening tool for comprehensive measurement of epigenetic modifications. Such a screen in any disease or exposure of interest would be of great utility for a broad range of human health studies. The interpretation of human epigenetic data generated using genome-scale approaches is hampered by three main obstacles. Firstly, available data are largely based on methylation differences measured in DNA obtained cross-sectionally at different ages throughout the life course, yet DNA methylation marks are known to vary by age. Secondly, although methylation is known to vary by cell and tissue types, measurements are made in accessible peripheral cell types accessible from otherwise healthy individuals, and do not always correlate with those of cell types that contribute to obesity. Thirdly, alteration to epigenetic marks can be caused by obesity, and this temporal ambiguity between exposure and outcome complicates causal inference. To overcome these obstacles, we will comprehensively identify regulatory DNA methylation for imprinted genes, creating the first draft of the human “imprintome”. Epigenetically regulated imprinted genes are estimated to comprise 1-2% (200-400 genes) of the human genome, and are critical in the development of the early embryo; however, only ~30 imprint control regions (ICRs), regulating 70-80 genes, are known. Monoallelic expression of imprinted genes is regulated by parent- of-origin specific DNA methylation at ICRs that is established prior to germ-layer specification and maintained in somatic tissues throughout life. Therefore, methylation marks regulating the expression of these genes are functionally relevant, and are conserved across cell types, among individuals, and throughout aging. These unique features of ICRs provide a means to a comprehensive tool for multiplexed measurement of early acquired epigenetic modifications, and assess their link between exposures and disease. Our overarching goal is to use genomewide approaches to systematically identify all ICRs using a wide variety of samples, including multiple cell types from males and females from a wide age range. In this way, identification can be restricted to only differentially methylated regions (DMRs) that are consistent across cell type, sex, and age – the hallmark of ICRs. The ICR panel will then be evaluated in relationship to obesity, by identifying, in umbilical cord blood at birth, ICR patterns predictive of obesity later in childhood. Identifying altered imprint regulation will provide markers for prospective risk assessment, identify mechanisms contributing to obesity development, and inform future research into environmental exposures affecting obesity. Once developed, this ICR screening assay would also then be used to identify regions of early epigenetic perturbation associated with any disease or exposure, creating new opportunities for understanding the fetal origins of these conditions.

项目摘要/摘要 在过去的30年里，肥胖症患病率的快速增长导致了表观遗传机制的假设 环境线索和肥胖结果之间的中介联系。然而，改变肥胖的表观遗传区 风险在很大程度上仍是未知的。我们目前缺乏全面测量表观遗传修饰的筛查工具。 对任何疾病或感兴趣的暴露进行这样的筛查，对于广泛的人类健康研究将是非常有用的。这个 使用基因组规模的方法产生的人类表观遗传数据的解释受到三个主要障碍的阻碍。 首先，现有的数据很大程度上是基于在不同的不同时期获得的横截面DNA甲基化差异。 在整个生命过程中，DNA甲基化标记是不同的，但众所周知，DNA甲基化标记会因年龄而异。其次，尽管甲基化是 已知随细胞和组织类型的不同而变化，测量是在可从其他方式访问的外周细胞类型中进行的 而且并不总是与导致肥胖的细胞类型相关。第三，更改为 表观遗传标记可由肥胖引起，这种暴露和结果之间的时间性模糊使因果关系复杂化。 推论。为了克服这些障碍，我们将全面识别印记基因的调控DNA甲基化， 创作了人类“印迹集”的初稿。表观遗传调控的印记基因估计占1-2% (200-400个基因)，对早期胚胎的发育至关重要；然而，只有30个印记 调控70-80个基因的控制区(ICR)是已知的。印记基因的单等位基因表达受亲本- 在种子层规范之前建立的ICR的起源特异性DNA甲基化，并在体细胞中保持 整个生命中的纸巾。因此，调节这些基因表达的甲基化标记在功能上是相关的， 在细胞类型、个体之间和整个衰老过程中都是保守的。ICR的这些独特功能提供了一种手段 一种对早期获得的表观遗传修饰进行多重测量的综合工具，并评估它们之间的联系 暴露和疾病之间的关系。我们的首要目标是使用全基因组方法系统地识别所有ICR 使用了各种各样的样本，包括来自不同年龄范围的男性和女性的多种细胞类型。就这样， 鉴定只能限于差异甲基化区域(DMR)，这些区域在细胞类型、性别和 年龄--ICR的标志。ICR小组随后将通过识别脐带中的肥胖来评估与肥胖的关系 出生时的血液，ICR模式预示着童年后期的肥胖。识别更改的印记规则将提供标记 对于前瞻性风险评估，确定导致肥胖发展的机制，并为未来的研究提供信息 影响肥胖的环境暴露。一旦开发出来，这种ICR筛查试验也将被用于识别 与任何疾病或暴露相关的早期表观遗传扰动区域，为 了解这些疾病的胎儿起源。