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: 10655605
• 负责人: Cathrine Hoyo
• 金额: $ 59.81万
• 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/10655605
• 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; 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; Maps; 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; Specific qualifier value; Specimen; Testing; Tissues; Trace metal; Triglycerides; aged; bisulfite sequencing; cell type; clinically actionable; cohort; comorbidity; deep sequencing; environmental chemical; epigenome; fetal; genetic variant; genome-wide; histone modification; human tissue; imprint; 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.

项目总结/摘要 在美国和其他地方，肥胖症的流行率增加导致了一种假设，即表观遗传机制介导了肥胖症的发生。 环境因素与肥胖结果之间的关系。然而，改变肥胖风险的表观遗传区域仍然存在。 很大程度上是未知的，目前缺乏一个全面衡量表观遗传修饰的筛选工具， 阻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于 感兴趣的人将对广泛的人类健康研究有很大的用处。人类表观遗传学数据的解释 使用基因组规模方法产生的基因组数据受到几个障碍的阻碍。首先，现有数据主要基于 在整个生命过程中不同年龄段的DNA中测量的甲基化差异， 已知甲基化标记随年龄而变化。其次，在可接近的外周细胞中进行甲基化测量， 从其他健康个体可获得的类型，以及细胞类型之间表观遗传标记的变异性意味着， 来自这些细胞的测量值并不总是与来自导致疾病的细胞类型的测量值相关。最后， 表观遗传标记的改变可以由疾病引起，这种暴露和结果之间的时间模糊性 使因果推理复杂化。为了克服这些障碍，我们全面鉴定了DNA甲基化- 控制基因组印记基因的调控区域，绘制人类“印记基因组”的初稿。 据估计，表观遗传学调节的印迹基因占人类基因组的1-2%（200-400个基因），并且是 在早期胚胎的发育中至关重要;然而，只有~24个印记控制区（ICR），调节70至80个基因， 目前已定义。印迹基因的单等位基因表达受亲本特异性DNA甲基化的调节， 在胚层规范之前建立并在整个生命周期中保持在体细胞组织中的ICR。我们的总体 目标是利用新发现的ICR，开发一个自定义平台，用于测量人体标本中的ICR， 统计学上识别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，导致胎盘功能障碍。镉相关甲基化将 还可以检查与儿童代谢结果的关系。一旦开发出来，这个ICR定制平台将是无价的， 在鉴定与其他早期获得性疾病或暴露相关的发育表观遗传干扰区域时， 为早期发现和了解人类健康和疾病的胎儿起源创造了新的机会。