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.

在这种高风险的高奖励DP2应用中，我希望研究线粒体的核功能 代谢酶。目前文献的证据表明，许多线粒体酶是 位于核本地化，更属于癌症等疾病。但是，存在很大的差距 关于它们在细胞核和生物学功能中的空间分布的知识。我们相信核本地化 线粒体代谢酶的酶不是随机的，并且有必要的耦合与关键生物学 调节此过程的功能。在这项研究中，我们希望执行全面的功能 表征线粒体酶在细胞核中的空间和临时作用。我们的 初步发现确定了KREB的循环酶，例如刺刺酶（ACO2），α-酮谷氨酸（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 富集在癌细胞的核中。我们假设这些线粒体酶在 基于核的，尚待表征。我们假设它们充当大型酶 复杂的复合物是通过转录因子和核控因素招募到染色质的，以维持代谢压力 在基因转录期间遇到。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，我们设想详细介绍通过核推动其招募的顺序事件 染色质的因素及其在重编程转录机制中的作用，以驱动侵袭性癌症。这 是一个新的概念，由来自各个群体的孤立报告支持，但仍然相对出乎意料，并且 缺乏全面的机械研究。我们认为我们的研究结果将对 生物医学研究中的广泛重要问题，包括代谢性疾病和癌症。