Transgenerational epigenetic inheritance of longevity

这项建议的目标是探索人类遗传病的跨代表观遗传。 长寿。一个根本的问题是，影响人类寿命的表观遗传变化是否 父代仍然可以影响后代的寿命，甚至 当导致这些变化的因素不再存在时。虽然有一些证据 对于简单性状的跨代表观遗传，我们知之甚少 关于后天获得的复杂性状的跨代遗传。了解 世代之间关于长寿的表观遗传记忆有可能带来革命性的 目前对复杂疾病的遗传范式也将有广泛的 对我们理解表观基因组重编程的影响。 我们最近有了一个令人惊讶的发现，特定调控因子的突变 双亲中组蛋白H3(H3K4me3)上的三甲基化赖氨酸4可延长小鼠的寿命 后代最多三代，即使在最初突变后也不再 现在时。这一意想不到的发现将我们的实验室引向了一个新的方向。我们的问题是 问：跨代表观遗传的潜在机制是什么？ 长寿？对寿命的表观遗传记忆可以推广到脊椎动物吗？可 影响衰老的环境因素，如饮食摄入量，会影响随后的衰老 世世代代，即使环境已经恢复正常？这种不同寻常的做法会不会 遗传模式在进化上的优势是“告知”子孙后代 关于祖先的环境？ 我们将开发一个创新和令人兴奋的框架来解决跨代问题 实验性的长寿遗传。一个主要目标将是系统地确定 以跨代的方式继承并调节这一过程的分子 无偏基因组学、蛋白质组学和代谢组学相结合的表观遗传记忆 技术和单细胞方法。另一个挑战将是研究 其他物种衰老和长寿的表观遗传记忆的重要性。我们有能力 使用互补的模式生物，包括蠕虫、短命的线虫 非洲剑鱼N.Furzeri和寿命更长的哺乳动物小鼠模型将特别 对这些研究有一定的帮助。 我们相信，这些研究将对我们的 探讨复杂疾病的病因学，包括糖尿病、癌症和 神经退行性疾病，并在发展新的预防和 这些疾病的治疗方法。我们的研究也将有广泛的和基础的 对表观基因组重编程和维护的基础生物学的影响 是发展和改进干细胞疗法和体外受精的关键一步。 项目说明

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 epigenetic memory of aging and longevity in other species. Our ability to use complementary model organisms, including the worm C. elegans, the short-lived African killifish N. furzeri, and longer-lived mammalian mouse models, will be particularly helpful for these studies. We believe that these studies will have a transformative impact on our way of approaching the etiology of complex diseases, including diabetes, cancer, and neurodegenerative disorders, and in developing new modes of prevention and treatments for these diseases. Our studies will also have broad and fundamental implications on the basic biology of epigenome reprogramming and maintenance, which is a crucial step in developing and improving stem cell therapies and in vitro fertilization. Project Description