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：
10032890
负责人：
ROBERT A WATERLAND
金额：
$ 50.01万
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/10032890
关键词：
Affect Area Assisted Reproductive Technology Base Sequence Beds Catalogs Cells Cleft Palate DNA DNA Methylation DNA Sequence Data Data Set Development Developmental Biology Diet Dietary Supplementation Disease Elements Embryo Environment Epigenetic Process Etiology Exhibits Foundations Gene Expression Gene Expression Profiling Genes Genetic Genetic Fingerprintings 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 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.

项目摘要（摘要）除了遗传学和环境外，表观遗传调节的个体差异可能决定肥胖。杰出的基因组环境称为亚稳态的乳头，为测试这一点提供了前所未有的机会。亚稳态 - 基本上是表观遗传多态性 - 暴露于DNA中的个体差异甲基化既不是组织特异性也不是遗传介导的。首先发现了亚稳态的乳头在小鼠中观察到剧烈的表型变异时，小鼠在小鼠中。在过去的十年中开创了人类亚稳态的发现和表征。我们已经证明了DNA 多个个体中多个时间安排的甲基化分析是确定区域的有效方法在DNA甲基化（亚稳态的标志）中表现出全身性跨性别变化。现在我们知道表观遗传亚稳定性对于小鼠和人类是共同的，必须识别和探索完整鼠标中的MES范围。因此，我们建议追求以下具体目标：目标1-执行小鼠亚稳态的无偏屏幕。 AIM 2-测试母校饮食甲基供体的影响补充后代DNA甲基化在亚稳态的乳链中。目标3：使用比较基因组学识别序列确定表观遗传亚能的性能。这些目标的成功完成将提供小鼠开发的基础（以及潜在的其他哺乳动物）模型，该模型将启用受控的实验，以帮助了解DNA甲基化的个体差异如何影响人类疾病。