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的基本机制， 成为长寿的关键决定因素。最近的研究结果在C.秀丽线虫提供了强有力的证据 表观遗传机制，特别是染色质调节，密切参与寿命的决定 及其继承。尽管有令人兴奋的生物学数据，表观遗传调控的机制 对寿命的影响尚不清楚。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寿命。这一提议的首要假设是 我们可以通过研究， 长寿突变体与破坏表观遗传机制，并通过探索如何整体表观遗传景观 随着年龄的变化，在强大的模型C。优雅基于我实验室最近的发现，我们将继续 三个具体目标。在目的1中，我们将研究推定的H3 K9 me 3 甲基转移酶SET-9和SET-26限制寿命并维持种系永生。我们建议 确定它们作用的长寿途径，确定蛋白质结构域和组织特异性， 作用，并绘制其全基因组结合谱和转录输出。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，我们将研究 H3 K36 me 3在年龄依赖性基因调控和长寿中的作用。我们建议研究 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变化， 确定识别H3 K36 me 3标记的因素，并监测消耗的生物后果 特定细胞/组织中的H3 K36甲基化。H3 K36 me 3是一种普遍存在的组蛋白修饰，因此阐明了它的 通过衰老过程中基因表达调控的机制将提供重要的新见解， 不仅是衰老生物学，而且是基因调控的基本机制。在目标3中，我们将研究 染色质景观如何随年龄变化。目前还不太了解衰老如何影响 C.优雅我们建议分析几个关键的基因组模式， 组蛋白修饰，以及核小体密度，通过老化过程，并使用计算 揭示年龄依赖模式的方法，可以为未来的研究产生可检验的假设。结果 将为整合新兴功能提供一个急需的框架 数据来了解表观基因组如何调节C.优雅中生成的数据 这一目标也将成为衰老和基因调控研究界的有用资源。拟议 这项研究将为表观遗传机制如何影响衰老和长寿提供实质性的新见解， 关键模式生物C.线虫，并将更广泛地影响对表观遗传基础的理解， 在不同的生物体中的寿命。

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.