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.

项目概要环境营养素的可用性和新陈代谢深刻影响个人的健康，而放松管制营养信号传导导致许多疾病，包括癌症。调节表观基因组以影响细胞表型和功能，但机制解释了营养物质如何缺乏表观基因组信号的定义是一个关键的科学问题。通过定义这些机制，我们将了解营养暴露如何影响健康，以及异常的营养信号传导如何导致疾病。雷帕霉素复合物 1 的机制目标。 (mTORC1) 是一种进化上保守的营养激活信号通路，可对多种信号做出反应。营养和代谢输入促进细胞生长和增殖，并且在癌症和其他疾病中失调虽然 mTORC1 是一种新兴的表观遗传调节因子，但它如何向表观基因组发出信号尚不清楚。在这个项目中，我们将使用酵母模型来定义这些机制，以我们之前的成功为基础。我们将测试 TORC1 信号传导控制结构染色质结合的总体假设在营养应激期间保持活力并调节代谢基因的蛋白质和组蛋白阅读器蛋白质在目标 I 中，我们将确定作用于组蛋白 H3 的特定表观遗传途径，促进组蛋白 H3 的结合。高迁移率族盒 (HMGB) 蛋白与染色质结合，以防止细胞在营养应激条件下死亡。然后，我们将从生化和遗传学角度定义非染色质结合的 HMGB 蛋白如何导致细胞死亡在 TORC1 应激期间，应激的人类细胞将 HMGB1 从染色质中驱逐出来，从而影响细胞质代谢。活性，启动先天免疫信号和炎症，并促进肿瘤发生。将识别保守的表观遗传途径，这些途径对于在 mTORC1 期间将 HMGB1 保留在染色质上至关重要 Aim II 将使用蛋白质组学和基因组学来防止这种 HMGB1 引起的病理效应。确定酵母 TORC1 如何抑制保守的 Sirtuin 组蛋白脱乙酰酶活性以调节的方法组蛋白阅读器染色质结合并控制线粒体转录代谢。评估这些组蛋白阅读器蛋白如何转录调节代谢基因的机制研究通过该项目的结论，我们将定义所使用的新颖且保守的机制。 TORC1 修饰表观基因组，防止营养应激期间细胞死亡并调节代谢基因这些机制将直接关系到理解人类 mTORC1 失调的机制。改变表观基因组以引起疾病。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The STAT3-Regulated Autophagy Pathway in Glioblastoma.

胶质母细胞瘤中 STAT3 调节的自噬途径。

DOI：
发表时间：
2023-04-29
期刊：
影响因子：
0
作者：
Laribee, Ronald Nicholas;Boucher, Andrew B;Madireddy, Saivikram;Pfeffer, Lawrence M
通讯作者：
Pfeffer, Lawrence M

Ccr4-Not ubiquitin ligase signaling regulates ribosomal protein homeostasis and inhibits 40S ribosomal autophagy.

Ccr4-Not 泛素连接酶信号传导可调节核糖体蛋白稳态并抑制 40S 核糖体自噬。

DOI：
发表时间：
2023-08-28
期刊：
影响因子：
0
作者：
Johnson, Daniel L;Kumar, Ravinder;Kakhniashvili, David;Pfeffer, Lawrence M;Laribee, R Nicholas
通讯作者：
Laribee, R Nicholas