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：
10442527
负责人：
Cathrine Hoyo
金额：
$ 59.1万
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/10442527
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.

项目摘要/摘要在过去30年中，肥胖症患病率的迅速增加导致了表观遗传机制的假设介导环境线索与肥胖结果之间的关联。然而，改变肥胖的表观遗传区域风险基本上是未知的。目前，我们缺乏对表观遗传修饰进行全面测量的筛选工具。对于任何疾病或感兴趣的暴露，这种屏幕对于广泛的人类健康研究都将是极大的实用性。通过基因组规模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，可用的数据主要基于在不同的DNA中测得的甲基化差异在整个生命过程中的年龄，但已知DNA甲基化标记会因年龄而异。其次，尽管甲基化是已知因细胞和组织类型而变化，在可访问的外围细胞类型中进行测量健康的个体，并且并不总是与导致肥胖的细胞类型的人相关。第三，改变表观遗传标记可能是由肥胖引起的，暴露与结果之间的暂时歧义使休闲复杂推理。为了克服这些障碍，我们将全面识别出印迹基因的调节性DNA甲基化，创建人类“ Indrantome”的初稿。表观遗传调节的印迹基因估计完成1-2％人类基因组的（200-400基因），对于早期胚胎的发展至关重要；但是，只有〜30个烙印控制区（ICR），控制70-80个基因。烙印基因的单相表达受父母的调节在ICRS处的原生素特异性DNA甲基化，该甲基化是在细菌层规范之前建立的，并保持在体细胞中一生的组织。因此，甲基化标记调节这些基因的表达在功能上相关，并且在个体和整个衰老之间跨细胞类型配置。 ICR的这些独特功能提供了一种手段为综合的工具，用于对早期获得的表观遗传修饰进行多重测量，并评估其链接在暴露与疾病之间。我们的总体目标是使用全基因组的方法系统地识别所有ICR 使用各种样本，包括来自男性和女性的多种细胞类型。这样，识别只能仅限于不同的甲基化区域（DMR），这些区域在细胞类型，性别和年龄 - ICR的标志。然后，将通过在脐带中识别与肥胖的关系评估ICR面板出生时的血液，ICR模式可预测儿童晚期的肥胖症。确定改变的烙印法规将提供标记进行预期风险评估，确定有助于肥胖发展的机制，并为未来的研究提供信息影响对象性的环境暴露。一旦开发，此ICR筛选测定也将用于识别与任何疾病或暴露有关的早期表观遗传扰动的区域，为了解这些条件的胎儿起源。