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）

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要美国和其他地区肥胖患病率的增加引发了这样的假说：表观遗传机制介导然而，改变肥胖风险的表观遗传区域仍然存在。很大程度上未知，目前缺乏全面测量表观遗传修饰的筛选工具妨碍了相关区域的识别。这种筛查也可以应用于任何疾病或暴露。兴趣对于广泛的人类健康研究具有很大的用途。使用基因组规模方法产生的结果受到几个障碍的阻碍：首先，现有数据很大程度上是基于现有数据的。在整个生命过程中不同年龄的横截面中测量 DNA 的甲基化差异，但 DNA 其次，甲基化标记会随着年龄的变化而变化，甲基化测量是在可接近的外周细胞中进行的。可从其他健康个体获得的类型，以及细胞类型之间表观遗传标记的变异性意味着这些细胞的测量结果并不总是与导致疾病的细胞类型的测量结果相关。表观遗传标记的改变可能是由疾病引起的，并且暴露和结果之间的这种时间模糊性为了克服这些障碍，我们全面鉴定了 DNA 甲基化—— 基因组印记基因的受控调控区域，绘制了人类“印记组”的初稿。据估计，表观遗传调节的印记基因占人类基因组的 1-2%（200-400 个基因），并且是对早期胚胎的发育至关重要；然而，只有约 24 个印记控制区 (ICR)，调节 70 至 80 个基因，目前已定义印记基因的单等位基因表达受亲本特异性DNA甲基化的调节。 ICR 在胚层规范之前就已建立，并在整个生命过程中维持在体细胞组织中。目标是利用新发现的 ICR，开发一个定制平台来测量人体样本中的 ICR，以及令人惊叹地识别出与最常见的痕量金属之一镉相关的人类印记组的子集，一种被胎盘隔离的重金属，会导致与镉相关的甲基化功能障碍。一旦开发完成，这个 ICR 定制平台将具有无价的价值。在与其他早期获得性疾病或暴露相关的发育表观遗传扰动区域，为早期检测和了解人类健康和疾病的胎儿起源创造新的机会。