Novel imprint control regions (ICRs) responsive to environmental exposures

响应环境暴露的新型印记控制区域（ICR）

• 批准号: 10296917
• 负责人: Cathrine Hoyo
• 金额: $ 62.31万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10296917
• 关键词: 5 year old; Adolescent; Affect; Age; Alanine Transaminase; Alleles; Bioinformatics; Biological Assay; Birth; Blood Pressure; Body mass index; Body measure procedure; Cadmium; Cells; Central obesity; Child; Childhood; Chromatin Structure; Chromosome Mapping; Chronic Disease; Communities; Consensus; CpG dinucleotide; Cues; Custom; Cytosine; DNA; DNA Methylation; Data; Deposition; Desire for food; Development; Disease; Early Diagnosis; Ectoderm; Elements; Embryo; Embryonic Development; Endoderm; Environmental Exposure; Environmental Pollutants; Epidemiology; Epigenetic Process; Exposure to; Fatty acid glycerol esters; Functional disorder; GRB10 gene; Gene Dosage; Gene Expression; Genes; Genetic; Genome; Genomic Imprinting; Germ Cells; Germ Layers; Goals; Growth; Growth Disorders; H19 gene; Health; Heavy Metals; Human; Human Genome; Hyperglycemia; Hyperlipidemia; Hypertension; IGF2 gene; Individual; Knowledge; Life; Life Cycle Stages; Link; Lipids; Liver Dysfunction; Measurement; Measures; Mediating; Mesoderm; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Methods; Methylation; Modification; Molecular Profiling; Nucleic Acid Regulatory Sequences; Nutrient; Obesity; Outcome; PLAGL1 gene; Parents; Pathway interactions; Peripheral; Placenta; Prevalence; Protocols documentation; Proxy; Records; Reporting; Role; Sampling; Satiation; Screening procedure; Site; Somatic Cell; Specimen; Testing; Tissues; Trace metal; Triglycerides; aged; base; bisulfite sequencing; cell type; clinically actionable; cohort; comorbidity; deep sequencing; environmental chemical; epigenome; fetal; genetic variant; genome-wide; histone modification; human tissue; imprint; individual variation; interest; non-alcoholic fatty liver disease; novel; obesity risk; offspring; prehypertension; prenatal; prenatal exposure; preservation; response; toxic metal; whole genome

PROJECT SUMMARY/ABSTRACT The increased prevalence of obesity in the US and elsewhere has led to the hypothesis that epigenetic mechanisms mediate associations between environmental cues and obesity outcomes. However, epigenetic regions that alter obesity risk are still largely unknown, and the current lack of a screening tool for comprehensive measurement of epigenetic modifications hampers the identification of associated regions. Such a screen that could also be applied to 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 several obstacles. Firstly, the 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, methylation measurements are made in accessible peripheral cell types accessible from otherwise healthy individuals, and variability of epigenetic marks between cell types means that measurements from these cells do not always correlate with those from cell types that contribute to diseases. Finally, alteration to epigenetic marks can be caused by disease, and this temporal ambiguity between exposure and outcome complicates causal inference. To overcome these obstacles, we have comprehensively identified DNA methylation- controlled regulatory regions for genomically imprinted genes, mapping the first draft of the human “imprint-ome”. 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 ~24 imprint control regions (ICRs), regulating 70 to 80 genes, are presently defined. Monoallelic expression of imprinted genes is regulated by parent-of-origin specific DNA methylation at ICRs that are established prior to germ-layer specification and maintained in somatic tissues throughout life. Our overarching goal is to leverage the newly identified ICRs, to develop a custom platform for measuring them in human specimens, and statistically identify the subset of the human imprint-ome associated with one of the most common trace metals—cadmium, a heavy metal that is sequestered by the placenta, contributing to placental dysfunction. Cadmium related methylation will also be examined in relation to children’s metabolic outcomes. Once developed, this ICR custom platform will be invaluable in identifying regions of developmental epigenetic perturbation associated with other early-acquired diseases or exposures, creating new opportunities for early detection and understanding the fetal origins of human health and disease.

项目摘要/摘要 美国和其他地方肥胖的患病率提高导致了一个假设，即表观遗传机制介导 环境线索与肥胖结果之间的关联。但是，改变肥胖风险的表观遗传区域仍然是 在很大程度上未知，目前缺乏筛选工具来全面测量表观遗传修饰 阻碍了相关区域的识别。这样的屏幕也可以应用于任何疾病或暴露 对于广泛的人类健康研究，兴趣将非常有用。人类表观遗传数据的解释 使用基因组尺度方法产生的几个障碍会阻碍。首先，可用数据主要基于 关于在整个生命过程中在不同年龄横截面获得的DNA中测得的甲基化差异，但DNA 已知甲基化标记因年龄而异。其次，在可访问的外围细胞中进行甲基化测量 从其他健康的个体中可以访问的类型，细胞类型之间的表观遗传标记的可变性意味着 这些细胞的测量并不总是与有助于疾病的细胞类型的细胞类型相关。最后， 表观遗传标记的改变可能是由疾病引起的，暴露与结果之间的暂时歧义 使因果推断复杂化。为了克服这些障碍，我们全面识别了DNA甲基化 - 基因上烙印基因的受控调节区域，绘制了人类“烙印”的初稿。 表观遗传调节的印迹基因估计完成了1-2％（200-400个基因），并且是人类基因组的。 早期胚胎的发展至关重要；但是，只有〜24个烙印控制区（ICR），调节70至80个基因， 提出了定义。印迹基因的单相表达受原始特异性DNA甲基化的调节 在生殖器规格之前建立的ICR，并在整个生命中保持在体细胞中。我们的总体 目标是利用新近确定的ICRS，开发一个自定义平台，以在人类标本中进行测量，并且 从统计上识别与最常见的痕量金属之一（cadmium）相关的人类烙印的子集 由胎盘隔离的重金属，导致胎盘功能障碍。镉相关的甲基化将 也可以根据儿童的代谢结果进行检查。一旦开发，此ICR自定义平台将是无价的 在确定与其他早期疾病或暴露相关的发育表观遗传扰动的区域时， 为早期发现和理解人类健康和疾病的胎儿起源创造新的机会。