Transgenerational epigenetic inheritance of longevity

描述 摘要： 这项提议的目标是探索长寿的跨代表观遗传。一个根本的问题是，即使导致这些变化的因素不再存在，影响父代寿命的表观遗传变化是否仍然会影响后代的寿命。虽然有一些简单性状的跨代表观遗传的证据存在，但对后天获得的复杂性状的跨代遗传知之甚少。理解世代之间长寿的表观遗传记忆有可能彻底改变目前关于复杂疾病遗传的范式，也将对我们理解表观基因组重新编程产生广泛的影响。我们最近有了一个令人惊讶的发现，父母中组蛋白H3(H3K4me3)上三甲基化赖氨酸4(H3K4me3)特定调节器的突变会导致后代的寿命延长多达三代，即使最初的突变不再存在。这 意想不到的发现将我们的实验室引向了一个新的方向。我们问的问题是：长寿的跨代表观遗传背后的机制是什么？对寿命的表观遗传记忆可以推广到脊椎动物吗？即使环境恢复正常，影响衰老的环境因素，如饮食摄入量，是否也会影响后代？这种非传统的遗传模式会不会具有让后代了解祖先所处环境的进化优势呢？我们将开发一个创新和令人兴奋的框架，以试验性的方式解决长寿的跨代遗传问题。一个主要目标将是系统地识别以跨代方式遗传的分子，并通过结合无偏见的基因组学、蛋白质组学和代谢组学技术以及单细胞方法来调节这种表观遗传记忆。另一个挑战将是检查epignet的重要性

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