Determining the Sub-Cellular Organelles that Link Lipid Signaling and Epigenetics

确定连接脂质信号传导和表观遗传学的亚细胞器

• 批准号: 9763211
• 负责人: Matthew D Hirschey
• 金额: $ 21万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763211
• 关键词: ATP Citrate (pro-S)-Lyase; Acetyl Coenzyme A; Acetylation; Adverse event; Affect; Animals; Applications Grants; Biological Models; CRISPR screen; Candidate Disease Gene; Caprylates; Carbon; Catabolism; Cell Cycle; Cell Cycle Inhibition; Cell Line; Cell Nucleus; Cell Proliferation; Cell model; Cell physiology; Cells; Chromatin; Citrates; Cleaved cell; Collaborations; Communication; Data; Deposition; Diet; Dietary Intervention; Disease; Endoplasmic Reticulum; Enzymes; Epigenetic Process; Event; Fatty Acids; Future; Gene Activation; Gene Expression; Gene Expression Profile; Generations; Genes; Glucose; Glycolysis; Goals; Health; Health Benefit; Histone Acetylation; Histones; Human; In Vitro; Incidence; Intelligence; Knock-out; Knowledge; Lead; Link; Lipids; Location; Lysine; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Mediator of activation protein; Medium chain triglycerides; Metabolic; Metabolism; Mitochondria; Molecular; Monitor; Nuclear; Nutrient; Organelles; Outcome; Oxides; Pathway interactions; Pharmacology; Play; Post-Translational Protein Processing; Prevention therapy; Production; Protein Isoforms; Proteins; Public Health; Publishing; Recurrence; Reporting; Repression; Role; Serum; Signal Transduction; Site; Source; Starvation; System; Testing; Therapeutic; Tumor Burden; Universities; Wood material; Work; biological adaptation to stress; cancer prevention; cancer therapy; cdc Genes; detection of nutrient; epidemiology study; epigenome; gene induction; genetic approach; glucose metabolism; histone modification; improved; innovation; lipid mediator; lipid metabolism; mouse model; novel; nutrient metabolism; oxidation; oxidized lipid; peroxisome; pre-clinical; prevent; programs; response; stable isotope; therapy design; treatment response; treatment strategy

Cells integrate nutrient sensing and metabolism to coordinate proper cellular responses to a particular nutrient source. For example, glucose drives a gene expression program characterized by activating genes involved in its metabolism, in part, by increasing glucose-derived histone acetylation. We recently expanded the known metabolites that integrate into epigenetic signaling and found that medium-chain lipid-derived acetyl-CoA is a major source of carbon for histone acetylation. This signaling axis leads to activation of stress response genes, including lipid metabolic genes, and inhibition of cell cycle gene expression. Our preliminary data presented in this application expand upon these gene expression observations and reveal lipid oxidation induces potent suppression of the cell cycle, lowers cellular proliferation across a range of cell lines, and lowers tumor burden in a mouse model of liver cancer. However, a critical gap in our knowledge remains that prevent us from fully understanding how the role of lipids and their oxidation in cancer: In which sub-cellular organelle are medium-chain lipids oxidized to generate acetyl-CoA for histone acetylation? Is the oxidation of MCTs required for their effect on cellular proliferation? What are the key cellular mediators of these epigenetic signals? There is a critical need to understand the full range of lipid’s molecular effects in order to enable more intelligent therapies for cancer. Although it is widely accepted that mitochondria oxidize lipids and are prime candidate sites of mediating communication between nutrients and the nucleus, no data exist to support this notion. Therefore, the single objective of this exploratory grant application is to determine the site(s) and molecular mediators of lipid signaling on epigenetics. Aim 1 will test three candidate sites of lipid metabolism using a combination of pharmacological and genetic approaches. In a complementary parallel approach, Aim 2 will perform an unbiased CRISPR- Cas9 screen to identify genes that are required for the suppressive effects of medium-chain lipids on cellular proliferation. This project is significant because it will explain the molecular mechanisms by which lipids and their oxidation mediate the positive effects cellular proliferation and cancer outcomes. We put forth conceptual and technical innovations that will both follow directed hypotheses and allow unbiased discovery of the most important aspects of the response to medium-chain lipids. Successful completion of this project will identify new aspects of inter- organelle communication in cancer.

细胞整合营养感测和代谢，以协调适当的细胞反应， 特殊的营养来源。例如，葡萄糖驱动基因表达程序，其特征在于 通过激活参与其代谢的基因，部分通过增加葡萄糖衍生的组蛋白， 乙酰化我们最近扩大了已知的代谢物，整合到表观遗传信号 并发现中链脂质衍生的乙酰辅酶A是组蛋白的主要碳源 乙酰化这个信号轴导致应激反应基因的激活，包括脂质 代谢基因和抑制细胞周期基因表达。我们的初步数据显示， 本申请扩展了这些基因表达观察，并揭示了脂质氧化 诱导细胞周期的有效抑制，降低一系列细胞的细胞增殖， 线，并降低肝癌小鼠模型中的肿瘤负荷。然而，我们的一个关键差距是， 知识仍然阻止我们充分理解脂质及其 氧化：在癌症中，亚细胞器中的中链脂质被氧化， 乙酰辅酶A用于组蛋白乙酰化MCT的氧化是否是其对细胞的作用所必需的？ 扩散？这些表观遗传信号的关键细胞介质是什么？存在一个临界 我们需要了解脂质分子的全部作用，以便能够更智能地 治疗癌症的方法尽管线粒体氧化脂质并在体内发挥重要作用已被广泛接受， 候选网站的调解之间的沟通营养物质和细胞核，没有数据存在， 支持这一观点。因此，本探索性赠款申请的唯一目标是 确定表观遗传学上脂质信号传导的位点和分子介质。目标1将测试 使用药理学和遗传学相结合的脂质代谢的三个候选位点 接近。在一种互补的并行方法中，Aim 2将执行无偏见的CRISPR- Cas9筛选以鉴定中链脂质抑制作用所需的基因 对细胞增殖的影响。这个项目意义重大，因为它将解释 脂质及其氧化介导细胞增殖的积极作用的机制 和癌症的结果。我们提出了概念和技术创新， 有指导的假设，并允许无偏见的发现最重要的方面的反应 到中链脂质。成功完成这一项目将确定新的方面， 癌症中的细胞器通讯