Decoding the nuclear metabolic processes regulating gene transcription

解码调节基因转录的核代谢过程

• 批准号: 10001134
• 负责人: Subhamoy Dasgupta
• 金额: $ 252.3万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-07 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10001134
• 关键词: ATP Citrate (pro-S)-Lyase; Aconitate Hydratase; Automobile Driving; Biological Process; Biomedical Research; Cell Nucleus; Chromatin; Citrate (si)-Synthase; Communication; Complex; Coupled; Disease; Disseminated Malignant Neoplasm; Enzymes; Event; Gene Expression Profiling; Genes; Genetic Transcription; Glutarates; Growth; Knowledge; Literature; Malignant Neoplasms; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic stress; Metabolism; Mitochondria; Multienzyme Complexes; Nuclear; Oncogenic; Process; Proteomics; Reporting; Role; Signal Transduction; Spatial Distribution; base; cancer cell; chromatin immunoprecipitation; high reward; high risk; metabolomics; novel; pyruvate dehydrogenase; recruit; transcription factor; tumor progression

In this High Risk High Reward DP2 application I wish to investigate the nuclear functions of mitochondrial metabolic enzymes. It is quite evident from current literature that many of the mitochondrial enzymes are localized to the nucleus, more so in diseased conditions such as cancer. However, there is a significant gap in knowledge about their spatial distribution in the nucleus and biological function. We believe nuclear localization of mitochondrial metabolic enzymes is not random, and there is specific necessity coupled to critical biological functions that regulate this process. In this study we wish to perform a comprehensive functional characterization deciphering the spatial and temporal role of mitochondrial enzymes in the nucleus. Our preliminary findings identified Kreb’s cycle enzymes such as aconitase (ACO2), α-keto glutarate (AKG), and citrate synthase (CS); and glycolytic enzymes such as pyruvate dehydrogenase (PDH) and ATP-citrate lyase are enriched in the nucleus of cancer cells. We hypothesize these mitochondrial enzymes form complex in the nucleus based which is yet to be characterized. We hypothesize that they function as a large-multi enzyme complex which is recruited to chromatin by transcription factors and coregulators to sustain metabolic stress encountered during gene transcription. Using metabolomics, proteomics, chromatin immunoprecipitation and gene expression analysis, we envision detailing the sequential events driving their recruitment by nuclear factors on chromatin, and their role in reprogramming transcription machinery to drive aggressive cancer. This is a novel concept supported by isolated reports from various groups, yet remains relatively unexplored and a comprehensive mechanistic study is lacking. We envision findings from our study will have a major impact on broad important problems in biomedical research including metabolic disorders and cancer.

在这个高风险高回报 DP2 应用中，我希望研究线粒体的核功能 从目前的文献中可以明显看出，许多线粒体酶都是代谢酶。 局限于细胞核，在癌症等疾病中更是如此。然而，存在显着的差距。 关于它们在细胞核中的空间分布和生物功能的知识我们相信核定位。 线粒体代谢酶的变化不是随机的，并且存在与关键生物相关的特定必然性 在这项研究中，我们希望执行一个全面的功能来调节这个过程。 表征破译线粒体酶在细胞核中的空间和时间作用。 初步研究结果确定了克雷布氏循环酶，例如乌头酸酶 (ACO2)、α-酮戊二酸 (AKG) 和 柠檬酸合酶 (CS)；和糖酵解酶，例如丙酮酸脱氢酶 (PDH) 和 ATP-柠檬酸裂解酶 我们发现这些线粒体酶在癌细胞的细胞核中形成复合物。 我们发现它们作为一种大型多酶发挥作用。 由转录因子和共调节因子招募到染色质以维持代谢应激的复合物 使用代谢组学、蛋白质组学、染色质免疫沉淀和 基因表达分析，我们设想详细描述通过核驱动它们招募的连续事件 染色质上的因子，及其在重编程转录机制以驱动侵袭性癌症中的作用。 是一个新颖的概念，得到了各个团体的孤立报告的支持，但仍然相对未经探索，并且 缺乏全面的机制研究，我们预计我们的研究结果将对 生物医学研究中广泛的重要问题，包括代谢紊乱和癌症。