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

细胞将营养感知和新陈代谢结合在一起，以协调细胞对 独特的营养来源。例如，葡萄糖驱动一个基因表达程序，其特征是 通过激活参与其新陈代谢的基因，部分是通过增加葡萄糖衍生的组蛋白 乙酰化。我们最近扩展了整合到表观遗传信号中的已知代谢物 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，以及抑制细胞周期基因的表达。我们的初步数据显示在 这一应用在这些基因表达观察的基础上进行了扩展，并揭示了脂肪氧化 诱导对细胞周期的有效抑制，降低一系列细胞的细胞增殖 并在小鼠肝癌模型中降低肿瘤负担。然而，我们的一个关键差距是 仍然存在的知识阻碍了我们充分了解脂质和它们的作用 癌症中的氧化：亚细胞器中的中链脂质被氧化生成 组蛋白乙酰化的乙酰辅酶A？MCT是否需要氧化才能对细胞产生影响 扩散？这些表观遗传信号的关键细胞介体是什么？有一个关键的问题 需要全方位了解脂质的分子作用，才能使更智能 癌症的治疗方法。尽管人们普遍认为线粒体氧化脂质是最重要的 营养物质和细胞核之间的调节通讯的候选位置，没有数据存在 支持这一观点。因此，这项探索性拨款申请的唯一目标是 确定表观遗传学中脂质信号的位点(S)和分子介体。AIM 1将测试 结合药理学和遗传学研究脂代谢的三个候选位点 接近了。在互补的并行方法中，AIM 2将执行无偏见的CRISPR- Cas9筛选以确定中链脂肪抑制作用所需的基因 关于细胞增殖的研究。这个项目意义重大，因为它将解释分子 脂类及其氧化介导细胞增殖正性效应的机制 以及癌症的结果。我们提出的概念和技术创新都将紧随其后 有针对性的假设并允许不偏不倚地发现反应的最重要方面 到中链脂类。该项目的成功完成将确定国际关系的新方面。 癌症中的细胞器通讯。

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.