Transgenerational epigenetic inheritance of longevity

长寿的跨代表观遗传

• 批准号: 8545670
• 负责人: ANNE BRUNET
• 金额: $ 76.15万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8545670
• 关键词: Address; Affect; Aging; Back; Cells; Complex; Dietary intake; Disease; Environment; Environmental Risk Factor; Epigenetic Process; Future Generations; Generations; Genomics; Goals; Histone H3; Inherited; Lead; Longevity; Lysine; Mediating; Memory; Mutation; Parents; Proteomics; Technology; Vertebrates; abstracting; epigenome; innovation; metabolomics; trait

DESCRIPTION Abstract: The goal of this proposal is to explore the transgenerational epigenetic inheritance of longevity. A fundamental question is whether epigenetic changes that affect lifespan in the parental generation can still impact the lifespan of the subsequent generations even when the factors that led to these changes are no longer present. While some evidence of transgenerational epigenetic inheritance for simple traits exist, very little is known about the transgenerational inheritance of acquired complex traits. Understanding the epigenetic memory of longevity between generations has the potential to revolutionize the current paradigm on the inheritance of complex diseases and will also have a broad impact on our understanding of epigenome reprogramming. We recently made the surprising discovery that mutations in specific regulators of trimethylated lysine 4 on histone H3 (H3K4me3) in parents lead to lifespan extension in descendants for up to three generations, even after the initial mutation is no longer present. This unexpected discovery has led our lab in a new direction. The questions we ask are: what are the mechanisms underlying transgenerational epigenetic inheritance of longevity? Is epigenetic memory of lifespan generalizable to vertebrates? Could environmental factors that affect aging, such as dietary intake, impact subsequent generations even when the environment is back to normal? Could this unconventional mode of inheritance have the evolutionary advantage of 'informing' future generations about the ancestors' environment? We will develop an innovative and exciting framework to address transgenerational inheritance of longevity experimentally. A major goal will be to systematically identify the molecules that are inherited in a transgenerational manner and that mediate this epigenetic memory by combining unbiased genomics, proteomics and metabolomics technologies and single-cell approaches. Another challenge will be to examine the importance of epigenet

描述 抽象的： 该提议的目的是探索寿命的转世表观遗传遗传。一个基本问题是，即使导致这些变化的因素不再存在，影响父母生成寿命的表观遗传变化是否仍会影响后代的寿命。尽管存在一些对简单特征的跨代表观遗传遗传的证据，但对获得的复杂性状的转世遗传知之甚少。了解世代之间长寿的表观遗传记忆有可能彻底改变当前的复杂疾病遗传范式，并且还将对我们对表观基因组重编程的理解产生广泛的影响。我们最近提出了一个令人惊讶的发现，即在父母的组蛋白H3（H3K4me3）上，特定的三甲基化赖氨酸4的突变导致后代的寿命延长多达三代，即使初始突变不再存在。这 意外的发现导致我们的实验室朝着新的方向发展。我们提出的问题是：跨代表观遗传遗传的寿命遗传是什么？对脊椎动物的寿命的表观遗传记忆是否可以概括？即使环境恢复正常，影响衰老的环境因素（例如饮食摄入）也会影响后代吗？这种非常规性的继承方式是否可以具有“告知”后代有关祖先环境的进化优势？我们将开发一个创新且令人兴奋的框架，以实验地解决长寿的跨代遗传。一个主要目标是系统地识别以跨代方式遗传的分子，并通过结合无偏基因组学，蛋白质组学和代谢组学技术和单细胞方法来介导这种表观遗传记忆。另一个挑战将是检查Epigenet的重要性