Mechanisms of Target of Rapamycin Complex 1 Dependent Epigenetic Regulation

项目摘要 环境营养素的可利用性和新陈代谢深刻地影响个人的健康，而放松管制， 营养信号传导的异常会导致许多疾病，包括癌症。营养信号和代谢 调节表观基因组以影响细胞表型和功能，但解释营养物质如何 信号传递到表观基因组的信号。定义这些机制构成了一个关键的科学问题， 必须解决。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是如何导致疾病的雷帕霉素复合物1的机制靶点 mTORC1是一种进化上保守的营养激活信号通路。MTORC1响应不同的 营养和代谢输入，以促进细胞生长和增殖，它是失调，在癌症和其他 疾病虽然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 在这个项目中，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， 我们将测试总体假设，即TORC 1信号控制结构蛋白的染色质结合， 在营养胁迫期间维持活力并调节代谢基因的蛋白质和组蛋白阅读器蛋白质 表情在目的I中，我们将确定作用于组蛋白H3的特定表观遗传途径， 高迁移率族蛋白（HMGB）蛋白质染色质，以防止细胞死亡的营养胁迫条件下。 然后，我们将从生物化学和遗传学的角度来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。应激的人细胞从染色质中驱逐HMGB1以影响细胞质代谢 活性，启动先天免疫信号传导和炎症，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，这些途径对于在mTORC 1过程中将HMGB1保留在染色质上至关重要。 应激以防止这种HMGB1诱导的病理作用。Aim II将使用蛋白质组学和基因组学 确定酵母TORC 1如何抑制保守的沉默调节蛋白组蛋白去乙酰化酶活性以调节 组蛋白阅读器染色质结合和控制线粒体代谢转录。然后我们将表演 机制研究，以评估这些组蛋白阅读器蛋白如何转录调节代谢基因 表情通过该项目的结论，我们将定义新的和保守的机制， TORC1修饰表观基因组，防止营养胁迫期间细胞死亡，调节代谢基因 转录。这些机制将直接相关的理解人类mTORC 1失调 改变表观基因组导致疾病

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.