Genetic and Epigenetic Determinants of Longevity.

项目总结： 表观遗传调控是连接基因组与环境的基本机制，而且 成为长寿的关键决定因素。最近在线虫中的发现提供了强有力的证据 表观遗传机制，特别是染色质调节，与决定寿命密切相关。 以及它的继承权。尽管有令人兴奋的生物学数据，表观遗传调控的机制 对长寿的影响尚不清楚。这一应用的长期目标是阐明表观遗传调控如何 连接基因组和环境以调节寿命。这项提议的首要假设是 我们可以通过研究来获得表观遗传调控和寿命之间的联系的机械性见解 长寿突变体的表观遗传机制被破坏，并通过探索整体表观遗传格局如何 在强大的秀丽线虫模型中，随着年龄的变化。在我实验室最新发现的基础上，我们将继续 三个具体目标。在目标1中，我们将研究推测的H3K9me3病毒的机制 甲基转移酶SET-9和SET-26限制寿命并维持生殖系不朽。我们建议 确定它们的长寿途径，确定它们的蛋白质结构域和组织特异性 行动，并绘制其全基因组结合图谱和转录输出。拟议的调查 将揭示SET-9/26如何影响寿命和跨代遗传。在目标2中，我们将调查 H3K36me3在年龄依赖性基因调控和长寿中的作用。我们建议研究是否 改变的RNA聚合酶II介导的转录有助于年龄依赖性基因表达的变化， 确定识别H3K36me3标志的因素，并监测消耗的生物后果 H3K36在特定细胞/组织中的甲基化。H3K36me3是一种普遍存在的组蛋白修饰，从而阐明了其 衰老过程中基因表达调控机制将为我们提供重要的新见解 不仅是衰老生物学，还有基因调控的基本机制。在目标3中，我们将调查 染色质景观如何随着年龄的变化而变化。目前，关于老龄化对老年人的影响还知之甚少。 线虫的一般染色质景观。我们建议描绘几个关键基因的全基因组模式 组蛋白修饰，以及核小体密度，通过老化过程，并使用计算 方法揭示与年龄相关的模式，为未来的研究产生可检验的假设。发现 我们提议的调查将提供一个急需的框架来整合新兴的功能 以了解表观基因组如何调节线虫的衰老和寿命。中生成的数据 这一目标也将成为老龄化和基因调控研究社区的有用资源。建议数 研究将为表观遗传机制如何影响人的衰老和长寿提供实质性的新见解 关键的模式生物秀丽线虫，并将更广泛地影响对表观遗传学基础的理解 不同生物体的长寿。

Project Summary: Epigenetic regulation is a fundamental mechanism that bridges the genome with the environment, and is emerging as a key determinant of longevity. Recent findings in C. elegans have provided strong evidence that epigenetic mechanisms, in particular chromatin regulation, are intimately involved in longevity determination and its inheritance. Despite the exciting biological data, the mechanisms of how epigenetic regulation influences longevity are unclear. The long-term goal of this application is to elucidate how epigenetic regulation bridges the genome and the environment to modulate longevity. The overarching hypothesis of this proposal is that we can gain mechanistic insights into the connection of epigenetic regulation and longevity by studying longevity mutants with disrupted epigenetic mechanisms and by probing how the overall epigenetic landscape changes with age in the powerful model C. elegans. Building on recent discoveries in my lab, we will pursue three specific aims. In Aim 1, we will investigate the mechanisms by which the putative H3K9me3 methyltransferases SET-9 & SET-26 limit lifespan and maintain germline immortality. We propose to determine the longevity pathways they act in, identify the protein domains and the tissue specificity key to their action, and map their genome-wide binding profiles and transcriptional outputs. The proposed investigations will reveal how SET-9/26 influence longevity and transgenerational inheritance. In Aim 2, we will investigate the role of H3K36me3 in age-dependent gene regulation and longevity. We propose to examine whether altered RNA polymerase II-mediated transcription contributes to age-dependent gene expression changes, identify the factors that recognize the H3K36me3 mark, and monitor the biological consequence of depleting H3K36 methylation in specific cells/tissues. H3K36me3 is a ubiquitous histone modification, thus elucidating its mechanism in gene expression regulation through the aging process will provide important new insights into not only aging biology but also fundamental mechanisms of gene regulation. In Aim 3, we will investigate how the chromatin landscape changes with age. Currently not much is known about how aging impacts the general chromatin landscape in C. elegans. We propose to profile the genome-wide patterns of several key histone modifications, as well as nucleosome density, through the aging process, and use computational methods to uncover age-dependent patterns that can generate testable hypotheses for future studies. Findings from our proposed investigations will provide a much-needed framework for integrating emerging functional data to understand how the epigenome modulates aging and longevity in C. elegans. The data generated in this aim will also be a useful resource for the aging and gene regulation research community. The proposed research will provide substantial new insights into how epigenetic mechanisms influence aging and longevity in the key model organism C. elegans, and will more broadly impact the understanding of the epigenetic basis of longevity in diverse organisms.