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：
10378095
负责人：
ROBERT A WATERLAND
金额：
$ 43.19万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10378095
关键词：
Affect Area Assisted Reproductive Technology Base Sequence Beds Catalogs Cells Cleft Palate 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 Human Genome 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 Toxicology Variant base 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

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）除了遗传和环境之外，表观遗传调控的个体差异也可能决定患病风险。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。亚稳态表观等位基因——本质上是表观遗传多态性——表现出 DNA 的个体间变异首次发现既非组织特异性也非遗传介导的亚稳态表观等位基因。在过去的 10 年里，我们在近交系小鼠中观察到了显着的表型变异。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了DNA。对多个个体的多个组织进行甲基化分析是识别区域的有效方法 DNA 甲基化表现出系统性的个体差异，这是亚稳态表观等位基因的标志。知道表观遗传亚稳定性对于小鼠和人类来说是常见的，因此有必要识别和探索完整的表观遗传亚稳定性。因此，我们建议追求以下具体目标：目标 1 - 执行一项对小鼠亚稳态表观等位基因进行无偏筛选。目标 2 - 测试母体饮食甲基供体的影响。目标 3：使用比较基因组学来补充亚稳态表观等位基因的后代 DNA 甲基化。成功完成这些目标将提供确定表观遗传亚稳定性的序列决定因素。开发小鼠（以及可能的其他哺乳动物）模型的基础，这将使对照实验帮助了解 DNA 甲基化的个体差异如何影响风险人类疾病。