Genetic and Epigenetic Determinants of Longevity

项目摘要 表观遗传调控作为一种基本机制，将基因组与 环境，是长寿的关键决定因素。C.秀丽线虫使用表观遗传调节的保守模式， 包括组蛋白修饰和非编码RNA，具有较短的正常寿命和巨大的工具包， 分子和基因组分析，并代表了一个强大的模型，为解开的主要原则， 长寿的表观遗传基础这项应用的长期目标是阐明表观遗传调控是如何 连接基因组和环境来调节衰老。在这个提议中，我们建立在原始发现的基础上， 在我们的实验室，并将调查表观遗传调节和长寿之间的机械联系， C.使用三个特定目标的优雅。在目标1中，我们将研究SET-26， H3K4me3阅读器，调节α-16转录活性。我们最近发现，SET-26与 组蛋白修饰H3 K4 me3（组蛋白3赖氨酸4三甲基化）并需要DAF-16来调节应激 反应和寿命。在这个目标中，我们将测试募集到基因组中的H3K4me3位点是否是 SET-26的功能，以及SET-26是否与HCF-1协同调节靶基因处的HCF-16占据 发起人。我们的研究将阐明SET-26如何连接H3K4me3，一种高度保守的组蛋白修饰， 应激反应和衰老中高度保守的主转录因子β-16。在目标2中，我们 阐述组蛋白独特模式的分子特征和功能后果 老龄C.优雅我们实验室正在进行的调查显示， 老年人体细胞组蛋白修饰的变化模式。优雅具体来说，我们观察到 低H3K36me3和动态H3K4me3的组合模式，与活性相关的两个主要组蛋白标记， 基因表达，与RNA表达随年龄的变化密切相关。我们将调查这是否 一种独特的模式是组织特异性的，与生理老化相关，并反映了增加的隐蔽转录 随年龄我们还将进一步表征所观察到的抑制性H3K27me3和异染色质的增加， H3K9me3在特定染色体臂上随年龄的增加而增加。我们的研究将提供宝贵的资源， 社区，并将指出基因调控计划的关键老化。在目标3中，我们将研究 衰老中的兴奋效应的表观遗传机制。衰老中的兴奋效应，即短暂暴露于轻度压力 生命早期可以赋予生命后期改善的活力，这是众所周知的，但仍有很多关于 其长期有益效果的分子基础。我们将比较两个压力团， 被证明可以增加抗应激能力，改善蛋白质稳定，延长寿命。我们将调查 持续的转录变化，在初始应激暴露后很长时间内赋予保护作用， 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.