Unbiased identification and characterization of mouse metastable epialleles

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。

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.