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Unbiased identification and characterization of mouse metastable epialleles

小鼠亚稳态表观等位基因的公正鉴定和表征

基本信息

批准号：
10589102
负责人：
ROBERT A WATERLAND
金额：
$ 38.59万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10589102
关键词：
Acceleration Affect Area Assisted Reproductive Technology Base Sequence Beds Catalogs Cells Cleft Palate Conceptions DNA DNA Methylation DNA Sequence DNA methylation profiling Data Data Set Development Developmental Biology Dietary Supplementation Disease Elements Embryo Environment Epigenetic Process Etiology Exhibits Foundations Gene Expression Gene Expression Profiling Genes Genetic Genetic Polymorphism Genetic Variation Genomic Segment Genomic approach Genomics Germ Layers Human Inbred Mouse Individual Individuality Intracisternal A-Particle Elements Label Machine Learning Malignant Neoplasms Maps Mediating Metabolic Methylation Micronutrients Modeling Mus Nature Nutritional Nutritional Study Obesity Outcome Pancreas Paper Phenotype Reporting Research Personnel Retrotransposon Seminal Supplementation Tail Testing Time Tissue Sample Tissues Variant bisulfite sequencing catalyst cell type comparative genomics critical period dietary disorder risk early pregnancy embryo culture epigenetic regulation epigenetic variation experimental study genomic locus improved inter-individual variation metabolic phenotype mother nutrition mouse development mouse genome mouse model nonhuman primate nutrition obesity risk offspring peripheral blood transgenerational epigenetic inheritance whole genome

项目摘要

PROJECT SUMMARY (Abstract) In addition to genetics and environment, interindividual variation in epigenetic regulation may determine risk of obesity. Exceptional genomic loci called metastable epialleles offer unprecedented opportunities to test this. Metastable epialleles – essentially epigenetic polymorphisms – exhibit interindividual variation in DNA methylation that is neither tissue-specific nor genetically mediated. Metastable epialleles were first discovered in mice when dramatic phenotypic variation was observed amongst inbred mice. Over the last 10 years we pioneered the discovery and characterization of human metastable epialleles. We have shown that DNA methylation profiling of multiple tissues in multiple individuals is an effective approach to identifying regions that exhibit systemic interindividual variation in DNA methylation, a hallmark of metastable epialleles. Now that we know epigenetic metastability is common to mice and humans, it is essential to identify and explore the full range of MEs in the mouse. We therefore propose to pursue the following Specific Aims: Aim 1 - Perform an unbiased screen for mouse metastable epialleles. Aim 2 - Test for effects of maternal dietary methyl donor supplementation on offspring DNA methylation at metastable epialleles. Aim 3: Use comparative genomics to identify sequence determinants of epigenetic metastability. Successful completion of these Aims will provide the foundation for development of mouse (and potentially other mammalian) models which will enable controlled experiments to help understand how interindividual variation in DNA methylation affects risk of disease in humans.

项目概要（摘要）除了遗传和环境外，表观遗传调节中的个体间变异可能决定了肥胖被称为亚稳态表观等位基因的特殊基因组位点为测试这一点提供了前所未有的机会。亚稳定表观等位基因-本质上是表观遗传多态性-表现出DNA的个体间变异甲基化既不是组织特异性的，也不是遗传介导的。亚稳定表观等位基因首次被发现当在近交系小鼠中观察到显著的表型变异时，在过去的10年里，开创了人类亚稳态表观等位基因的发现和表征。我们已经证明DNA 在多个个体中的多个组织的甲基化谱是鉴定区域的有效方法，表现出DNA甲基化的系统性个体间变异，这是亚稳定表观等位基因的标志。现在我们我知道表观遗传亚稳定性在小鼠和人类中是共同的，因此有必要确定和探索整个亚稳定性。小鼠中的ME范围。因此，我们建议达致以下具体目标：目标1 - 小鼠亚稳定表观等位基因的无偏筛选。目标2 -测试母体膳食甲基供体的影响在亚稳态表观等位基因处对后代DNA甲基化的补充。目标3：利用比较基因组学鉴定表观遗传亚稳定性序列决定因素。成功实现这些目标将为小鼠（以及可能的其他哺乳动物）模型开发的基础，对照实验，以帮助了解DNA甲基化的个体间变异如何影响人类的疾病。