Genetic and Epigenetic Determinants of Longevity

项目摘要 表观遗传调控是连接基因组与 环境，是长寿的关键决定因素。线虫使用保守的表观遗传调控模式， 包括组蛋白修饰和非编码RNA，具有很短的正常寿命和大量的工具包 分子和基因组分析，并代表了一个强大的模型，以解开主要原则 长寿的表观遗传学基础。这一应用的长期目标是阐明表观遗传调控如何 在基因组和环境之间架起桥梁以调节衰老。在这个提案中，我们建立在原始发现的基础上 并将研究表观遗传调控与长寿之间的机制联系 线虫使用三个特定的目标。在目标1中，我们将研究SET-26、A H3K4me3阅读器，调节DAF-16转录活性。我们最近透露，SET-26与 组蛋白修饰H3K4me3(组蛋白3赖氨酸4三甲基化)并需要DAF-16来调节应激 响应和寿命。在这个目标中，我们将测试招募到基因组中的H3K4me3位点是否对 SET-26的功能以及SET-26是否与HCF-1协同调节DAF-16在靶基因上的占位 推动者。我们的研究将阐明SET-26如何将H3K4me3，一种高度保守的组蛋白修饰，以及 DAF-16，一个高度保守的主要转录因子，在应激反应和衰老中的作用。在目标2中，我们将 阐述组蛋白独特模式的分子特征和功能后果 高龄线虫的修饰变化。我们实验室正在进行的研究揭示了一个有趣的问题 老年线虫体细胞中组蛋白修饰模式的变化。具体地说，我们观察到 低H3K36me3和动态H3K4me3的组合模式，与活动性相关的两个主要组蛋白标志 基因表达与RNA表达随年龄的变化有很强的相关性。我们将调查这是否 独特的模式是组织特有的，与生理衰老相关，并反映了隐蔽转录的增加 随着年龄的增长。我们还将进一步表征观察到的抑制性H3K27me3和异染色质的增益 特定染色体臂上的H3K9me3随年龄增长。我们的研究将为 社区，并将指出对衰老至关重要的基因调控计划。在目标3中，我们将调查 衰老过程中兴奋作用的表观遗传学机制。衰老中的兴奋作用，即短暂暴露于轻度应激 生命早期可以在以后的生命中增强活力，这是众所周知的，但关于 其长期有益效果的分子基础。我们将对两个压力团体进行比较 证明能增强抗逆性，改善蛋白质平衡，延长寿命。我们将调查 持续的转录变化，在最初的应激暴露后很长一段时间内赋予保护作用，以及 染色质和转录因子，以及可能的组蛋白修饰，调节转录 记忆。

Project Summary Epigenetic regulation serves as a fundamental mechanism that bridges the genome with the environment, and is a key determinant of longevity. C. elegans uses conserved modes of epigenetic regulation, including histone modifications and non-coding RNAs, has a short normal lifespan and a vast toolkit for molecular and genomic analyses, and represents a powerful model for unraveling the major principles of the epigenetic basis of longevity. The long-term goal of this application is to elucidate how epigenetic regulation bridges the genome and the environment to modulate aging. In this proposal, we build on original discoveries made in our lab and will investigate the mechanistic connection between epigenetic regulation and longevity in C. elegans using three specific aims. In Aim 1, we will investigate the mechanisms by which SET-26, a H3K4me3 reader, regulates DAF-16 transcriptional activity. We recently revealed that SET-26 binds to the histone modification H3K4me3 (histone 3 lysine 4 trimethylation) and requires DAF-16 to modulate stress response and lifespan. In this aim, we will test whether recruitment to H3K4me3 sites in the genome is key for SET-26 functions, and whether SET-26 collaborates with HCF-1 to regulate DAF-16 occupancy at target gene promoters. Our study will illuminate how SET-26 links H3K4me3, a highly conserved histone modification, and DAF-16, a highly conserved master transcription factor, in stress response and aging. In Aim 2, we will elaborate the molecular characteristics and functional consequences of the unique patterns of histone modification changes in aged C. elegans. Ongoing investigations in our lab have revealed interesting patterns of histone modification changes in the somatic cells of aged C. elegans. Specifically, we observed a combined pattern of low H3K36me3 and dynamic H3K4me3, two major histone marks associated with active gene expression, to strongly correlate with RNA expression change with age. We will investigate whether this unique pattern is tissue-specific, correlates with physiological aging, and reflects increased cryptic transcription with age. We will also further characterize the observed gain of the repressive H3K27me3 and heterochromatin H3K9me3 on particular chromosome arms with age. Our study will provide an invaluable resource for the community and will point to the gene regulatory programs key to aging. In Aim 3, we will investigate the epigenetic mechanisms of hormesis in aging. Hormesis in aging, where transient exposure to a mild stress early in life can confer improved vitality later in life, is well known but much remains to be learnt about the molecular basis of its long-lasting beneficial effects. We will compare two stress regiments that have been demonstrated to increase stress resistance, improve proteostasis, and extend lifespan. We will investigate the sustained transcriptional changes that confer the protective effects long after the initial stress exposure, and the chromatin and transcription factors, and possible histone modifications, that regulate the transcriptional memory.