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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要过去 30 年肥胖患病率的迅速增加引发了这样的假说：表观遗传机制然而，改变肥胖的表观遗传区域介导了环境因素和肥胖结果之间的关联。我们目前缺乏全面测量表观遗传修饰的筛查工具。这种对任何感兴趣的疾病或暴露的筛查对于广泛的人类健康研究都将非常有用。使用基因组规模方法生成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，现有数据主要基于在不同时间获得的横截面 DNA 中测量的甲基化差异。其次，尽管甲基化是在整个生命过程中的年龄，但已知 DNA 甲基化标记会随年龄而变化。已知因细胞和组织类型而异，测量是在可从其他途径获得的外周细胞类型中进行的健康个体，并不总是与导致肥胖的细胞类型相关。表观遗传标记可能是由肥胖引起的，而暴露和结果并发症之间的这种时间模糊性是因果关系为了克服这些障碍，我们将全面识别印迹基因的调控DNA甲基化，创建人类“印记组”的第一稿。表观遗传调控的印记基因估计占 1-2%。人类基因组中的（200-400 个基因）对早期胚胎的发育至关重要，但只有约 30 个印记；已知控制区(ICR)调节70-80个基因，印记基因的单等位基因表达受亲本调节。 ICR 处的原产地特异性 DNA 甲基化在胚层规范之前就已建立并在体细胞中维持因此，调节这些基因表达的甲基化标记在功能上是相关的，并且 ICR 的这些独特特征在不同细胞类型、个体之间以及整个衰老过程中都是保守的。用于多重测量早期获得的表观遗传修饰的综合工具，并评估它们的联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。使用多种样本，包括来自不同年龄范围的男性和女性的多种细胞类型，识别可以仅限于差异甲基化区域 (DMR)，这些区域在细胞类型、性别和性别之间是一致的。然后，ICR 小组将通过识别脐带来评估年龄与肥胖的关系。出生时的血液、ICR 模式可预测童年后期的肥胖，从而提供标记。进行前瞻性风险评估，确定导致肥胖发展的机制，并为未来的研究提供信息一旦开发出影响肥胖的环境暴露，这种 ICR 筛查方法也将用于识别。与任何疾病或暴露相关的早期表观遗传扰动区域，为了解这些情况的胎儿起源。