Molecular mechanisms linking epigenetic changes to longevity

项目摘要 了解控制衰老过程的分子机制对于面对不断增加的 与年龄有关的疾病的发病率。随着年龄的增长，表观遗传调控的丧失已经成为衰老的标志， 但对于染色质改变与长寿之间的联系机制却知之甚少。最近，在与 在斯坦福大学的Brunet实验室，我们证明了秀丽隐杆线虫的染色质变化 生殖系，特别是组蛋白H3（H3 K4 me 3）上赖氨酸4通过复合蛋白的三甲基化缺陷 与Set 1（COMPASS）相关，诱导mTOR靶点表达的变化， 通过特定的单不饱和脂肪酸的富集，体细胞组织中的代谢转变以延长寿命 （MUFA）。这种作用是由SREBP 1/SBP-1转录因子介导的，该转录因子通过COPII-1激活。 介导的ER至高尔基体的转运。最近的哺乳动物数据强调了CREB调节的关键作用， 转录辅激活因子（CRTC）2在COPII运输中的作用，而我们已经证明，唯一的C.秀丽线虫CRTC 调节衰老和能量代谢。令人兴奋的是，我的初步数据表明，CRTC-1特别是 调节H3 K4 me 3缺陷动物的寿命延长，建立CRTC-1在表观遗传学中的新作用 调节衰老。我的长期目标是了解表观遗传调控如何整合环境和 影响基因表达和下游细胞过程的内部信号，以促进长寿， 跨代的好处。该提案将使用遗传学，显微镜，代谢组学和 基因组方法揭示介导H3 K4 me 3依赖性寿命的分子机制。要求1 将定义COMPASS染色质复合体的时空要求，以介导寿命及其 效应物如CRTC-1、SREBP 1/SBP-1和mTOR靶标。为了补充这些研究，目标2将确定 CRTC-1特定功能调节的下游分子机制和代谢变化， 促进H3 K4 me 3依赖性长寿。独立R 00阶段将重点研究跨代 COMPASS-mTOR-CRTC通路下游的机制，以促进长寿。养护 所有这些组件将允许我在这里将这些发现转化到哺乳动物系统中， 和生理反应，表观遗传修饰控制，以促进长寿。总之，这些发现 将作为我研究计划的基础，并将启动我独立研究的开始 事业我的主要导师，威廉·梅尔博士将提供重要的科学和职业指导，以确保我的 成功我的顾问和合作者补充了Mair博士的专业知识，并将帮助我实现我的职业生涯， 研究目标。K99/R 00奖为我在学术道路上的进步提供了一个独特的机会。它 将帮助我巩固衰老表观遗传学研究的创新利基，并为我提供 必要的学术和技术培训，以开始我作为独立调查员的职业生涯。

Project Summary Understanding molecular mechanisms that govern the aging process is critical in the face of the ever-increasing incidence of age-related diseases. Loss of epigenetic regulation with age has emerged as a hallmark of aging, but little is known about the mechanisms linking chromatin alterations to longevity. Recently, in collaboration with the Brunet lab at Stanford University, we demonstrated that chromatin changes in the Caenorhabditis elegans germline, specifically a deficiency in trimethylation of lysine 4 on histone H3 (H3K4me3) via the Complex Proteins Associated with Set1 (COMPASS), induce changes in expression of mTOR targets which orchestrate a metabolic shift in somatic tissues to extend lifespan via a specific enrichment of mono-unsaturated fatty acids (MUFAs). This effect is mediated by the SREBP1/SBP-1 transcription factor, which is activated through COPII- mediated ER-to-Golgi transport. Recent data in mammals highlighted a critical role for CREB regulated transcriptional coactivator (CRTC)2 in COPII trafficking, while we have shown that the sole C. elegans CRTC modulates aging and energetic metabolism. Excitingly, my preliminary data indicate that CRTC-1 specifically regulates lifespan extension in H3K4me3-deficient animals, establishing a novel role of CRTC-1 in the epigenetic regulation of aging. My long-term goal is to understand how epigenetic regulation integrates environmental and internal signals to influence gene expression and downstream cellular processes to promote longevity and transgenerational benefits. This proposal will use a combination of genetics, microscopy, metabolomics, and genomic approaches to uncover the molecular mechanisms that mediate H3K4me3-dependent longevity. Aim 1 will define the spatiotemporal requirements of the COMPASS chromatin complex to mediate longevity and its effectors such as CRTC-1, SREBP1/SBP-1 and mTOR targets. To complement these studies, Aim 2 will identify the downstream molecular mechanisms and metabolic changes that a specific function of CRTC-1 regulates to promote H3K4me3-dependent longevity. The independent R00 phase will focus on studying transgenerational mechanisms downstream of the COMPASS-mTOR-CRTC pathway to promote longevity. The conservation of all these components will allow me here to translate these findings into mammalian systems to identify the cellular and physiological responses that epigenetic modifications control to promote longevity. Together, these findings will serve as the foundation of my research program and will launch the beginning of my independent research career. My primary mentor, Dr. William Mair will provide important scientific and career guidance to ensure my success. My advisors and collaborators complement Dr. Mair’s expertise and will help me reach my career and research goals. The K99/R00 award constitutes a unique opportunity for my advance in the academic track. It will help me to consolidate an innovative niche in the study of epigenetics of aging and provide me with the necessary academic and technical training to launch my career as an independent investigator.