Unbiased identification and characterization of mouse metastable epialleles

项目摘要(摘要) 除了遗传和环境外，表观遗传调控中的个体间差异可能决定了 肥胖。被称为亚稳态表观等位基因的特殊基因组基因座提供了前所未有的机会来检验这一点。 亚稳态表观等位基因--本质上是表观遗传的多态--在DNA中表现出个体间的差异 甲基化既不是组织特有的，也不是基因介导的。亚稳性表位基因首次被发现 在近亲交配的小鼠中观察到显著的表型变化。在过去的10年里，我们 开创性地发现和表征了人类亚稳态表位基因。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 表现出DNA甲基化的个体间系统性变异，这是亚稳定表型等位基因的标志。现在我们 知道表观遗传亚稳定性在老鼠和人类中是常见的，识别和探索完整的 鼠标中的MES范围。因此，我们建议实现以下具体目标：目标1-执行 小鼠亚稳态表位基因的无偏筛选。目标2-母体膳食甲基供体的效果测试 亚稳态表观等位基因子代DNA甲基化的补充。目标3：使用比较基因组学来 确定表观遗传亚稳定性的序列决定因素。成功完成这些目标将提供 为开发小鼠(可能还有其他哺乳动物)模型奠定基础，这将使 帮助了解DNA甲基化个体间变异如何影响患病风险的对照实验 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.