Genetic and Epigenetic Determinants of Longevity

长寿的遗传和表观遗传决定因素

• 批准号: 10434913
• 负责人: Siu Sylvia Lee
• 金额: $ 54.82万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10434913
• 关键词: Age; Aging; Binding; Biological; Biological Phenomena; Biology of Aging; Caenorhabditis elegans; Cells; Characteristics; Chromatin; Chromatin Remodeling Factor; Chromosome Arm; Chronic stress; Communities; Complex; Coupled; DNA Methylation; DNA Sequence; Data; Development; Disease; Environment; Epigenetic Process; Exposure to; Future; Gene Expression; Generations; Genes; Genetic; Genetic Models; Genetic Transcription; Genome; Genomics; Goals; Health; Heritability; Heterochromatin; Histones; Homologous Gene; Inherited; Investigation; Life; Link; Longevity; Longevity Pathway; Lysine; Memory; Methyltransferase; Modeling; Modification; Molecular; Organism; Pattern; Physiologic pulse; Physiological; Process; Proteins; RNA Interference; Reader; Regulator Genes; Research; Resistance; Resources; Role; Site; Somatic Cell; Stress; Techniques; Testing; Tissues; Untranslated RNA; age related; aged; base; biological adaptation to stress; cell age; environmental intervention; environmental stressor; epigenetic regulation; experience; genomic data; healthy aging; histone modification; host cell factor C1; improved; insight; mutant; offspring; programs; promoter; protective effect; protein complex; proteostasis; recruit; therapeutic development; transcription factor; transgenerational epigenetic inheritance

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.

项目概要 表观遗传调控是连接基因组与生物体的基本机制。 环境，是长寿的关键因素。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，正常寿命较短，并且有一个庞大的工具包 分子和基因组分析，并代表了阐明主要原理的强大模型 长寿的表观遗传基础。该应用的长期目标是阐明表观遗传调控如何 连接基因组和环境来调节衰老。在这个提案中，我们以原创发现为基础 我们实验室制作的，将研究表观遗传调控与长寿之间的机制联系 线虫使用三个特定目标。在目标 1 中，我们将研究 SET-26（一种 H3K4me3 阅读器，调节 DAF-16 转录活性。我们最近透露 SET-26 结合 组蛋白修饰 H3K4me3（组蛋白 3 赖氨酸 4 三甲基化）并且需要 DAF-16 来调节应激 反应和寿命。为此，我们将测试基因组中 H3K4me3 位点的招募是否是关键 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）和 DAF-16 是一种在应激反应和衰老过程中高度保守的主转录因子。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 老年秀丽隐杆线虫的修饰变化。 Ongoing investigations in our lab have revealed interesting 老年秀丽隐杆线虫体细胞中组蛋白修饰变化的模式。具体来说，我们观察到 低 H3K36me3 和动态 H3K4me3 的组合模式，这是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 独特的模式是组织特异性的，与生理衰老相关，并反映了神秘转录的增加 随着年龄的增长。我们还将进一步表征抑制性 H3K27me3 和异染色质的观察到的增益 特定染色体臂上的 H3K9me3 随着年龄的增长。我们的研究将为以下领域提供宝贵的资源： 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 衰老过程中毒物兴奋效应的表观遗传机制。衰老过程中的毒物兴奋效应，即短暂暴露于轻微压力 生命早期可以赋予生命后期更好的活力，这是众所周知的，但仍有很多东西需要了解 其持久有益作用的分子基础。我们将比较两个已接受的压力团 被证明可以提高抗压能力，改善蛋白质稳态，并延长寿命。我们将调查 持续的转录变化在最初的压力暴露后很长时间内仍具有保护作用，并且 染色质和转录因子，以及可能的组蛋白修饰，调节转录 记忆。