Mechanisms of Target of Rapamycin Complex 1 Dependent Epigenetic Regulation

雷帕霉素复合物1依赖的表观遗传调控靶点机制

基本信息

批准号：
10653258
负责人：
Ronald Laribee
金额：
$ 30.8万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10653258
关键词：
Acetylation Address Affect Architecture Binding Biochemical Cell Death Cell Nucleus Cell Proliferation Cell Survival Cells ChIP-seq Chromatin Chromatin Structure Collaborations Complex Coupled Critical Pathways Cytoplasm Deacetylase Disease Engineering Environment Epigenetic Process FRAP1 gene Future Gene Expression Genes Genetic Genetic Screening Genetic Transcription Genomic approach Goals HMGB Family Gene HMGB1 gene Health Histone Acetylation Histone Deacetylase Histone H3 Histone H4 Histones Homeostasis Homologous Gene Human Immune signaling In Vitro Individual Inflammation Knowledge Libraries Link Lysine Malignant Neoplasms Metabolic Metabolic Control Metabolism Mitochondria Modeling Nutrient Nutrient availability Obesity Outcome Pathologic Pathway interactions Peptides Phenotype Post-Translational Protein Processing Process Proliferating Proteins Proteomics Reader Regulation Repression Role Signal Pathway Signal Transduction Sirolimus Sirtuins Site Stress Testing Transcriptional Regulation Work Yeast Model System Yeasts analog cell growth chemical genetics epigenetic regulation epigenome genetic analysis histone modification inhibitor mutant novel nutrient metabolism prevent success transmission process tumorigenesis

项目摘要

Project Summary Environmental nutrient availability and metabolism profoundly affects an individual’s health, while deregulation of nutrient signaling contributes to many diseases, including cancer. Nutrient signaling and metabolism regulate the epigenome to affect cellular phenotype and function, yet mechanisms explaining how nutrients signal to the epigenome are lacking. Defining these mechanisms constitutes a critical scientific problem that is essential to address. By defining these mechanisms, we will understand how nutrient exposures affect health, and how aberrant nutrient signaling causes disease. The mechanistic target of rapamycin complex 1 (mTORC1) is an evolutionarily conserved nutrient activated signaling pathway. MTORC1 responds to diverse nutrient and metabolic inputs to promote cell growth and proliferation, and it is deregulated in cancer and other diseases. While mTORC1 is an emerging epigenetic regulator, how it signals to the epigenome is unknown. In this project, we will use a yeast model to build on our previous successes to define these mechanisms. Herein, we will test the overarching hypothesis that TORC1 signaling controls the chromatin binding of architectural proteins and histone reader proteins that maintain viability during nutrient stress and regulate metabolic gene expression. In Aim I, we will identify specific epigenetic pathways acting on histone H3 that promote binding of high mobility group box (HMGB) proteins to chromatin to prevent cell death under nutrient stress conditions. We then will define biochemically and genetically how non-chromatin bound HMGB proteins cause cell death during TORC1 stress. Stressed human cells evict HMGB1 from chromatin to affect cytoplasmic metabolic activities, initiate innate immune signaling and inflammation, and promote tumorigenesis. These yeast studies will identify conserved epigenetic pathways that are critical for retaining HMGB1 on chromatin during mTORC1 stress to prevent such HMGB1-induced pathological effects. Aim II will use proteomic and genomic approaches to define how yeast TORC1 represses conserved sirtuin histone deacetylase activity to regulate histone reader chromatin binding and control mitochondrial metabolic transcription. We then will perform mechanistic studies to assess how these histone reader proteins transcriptionally regulate metabolic gene expression. By the project’s conclusion, we will have defined novel and conserved mechanisms used by TORC1 to modify the epigenome, which prevent cell death during nutrient stress and regulate metabolic gene transcription. These mechanisms will be directly relevant for understanding how human mTORC1 deregulation alters the epigenome to cause disease.

项目摘要环境营养的可用性和代谢对个人的健康产生深远影响，而放松管制营养信号传导有助于许多疾病，包括癌症。营养信号传导和代谢调节表观基因组以影响细胞表型和功能，但机制解释了营养的方式缺乏向表观基因组的信号。定义这些机制构成一个关键的科学问题，即必不可少的问题。通过定义这些机制，我们将了解营养暴露如何影响健康，以及营养信号的异常导致疾病。雷帕霉素复合物的机械靶标1 （MTORC1）是一种进化配置的营养活化信号通路。 MTORC1对潜水员做出回应营养和代谢输入以促进细胞生长和增殖，并在癌症和其他疾病。尽管MTORC1是一种新兴的表观遗传调节剂，但它如何向表观遗传组发出信号。在这个项目，我们将使用酵母模型来建立我们以前的成功来定义这些机制。在此处，我们将测试总体假设，即TORC1信号传导控制体系结构的染色质结合蛋白质和组蛋白读取子蛋白在营养应激期间保持生存能力并调节代谢基因表达。在目标I中，我们将确定作用于组蛋白H3的特定表观遗传途径，以促进结合高迁移率组盒（HMGB）蛋白与染色质蛋白，以防止在营养应激条件下细胞死亡。然后，我们将通过生化和普遍定义非染色质HMGB蛋白如何引起细胞死亡在TORC1应力期间。压力的人类细胞从染色质驱逐HMGB1来影响细胞质代谢活动，启动先天免疫信号传导和感染，并促进肿瘤发生。这些酵母研究将确定保守的表观遗传途径，这对于在MTORC1期间保留HMGB1至关重要压力以防止这种HMGB1诱导的病理作用。 AIM II将使用蛋白质组学和基因组学定义酵母托尔克1如何再现构成Sirtuin组蛋白脱乙酰基酶活性的方法组蛋白读取器染色质结合和控制线粒体代谢转录。然后我们将表演机械研究以评估这些组蛋白读取器蛋白如何转录调节代谢基因表达。根据该项目的结论，我们将定义新的和构成由 Torc1修改表观基因组，可防止营养应激期间细胞死亡并调节代谢基因转录。这些机制将与了解人类MTORC1放松管制直接相关改变表观基因组以引起疾病。