Epigenetic regulation by TOR signaling

TOR 信号传导的表观遗传调控

基本信息

批准号：
8189085
负责人：
Ronald Laribee
金额：
$ 16.26万
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：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8189085
关键词：
Acetylation Affect Antineoplastic Agents Binding Biochemical Biological Caloric Restriction Cell Proliferation Cells Chemicals Chromatin Chromatin Structure Clinical Research Complex Coupled Critical Pathways Cyclic AMP-Dependent Protein Kinases DNA DNA Polymerase I Data Disease Drug Delivery Systems Epigenetic Process Future Gene Expression Gene Mutation Genes Genetic Genetic Screening Genetic Transcription Genomics Goals Health Histone H3 Histone H4 Histones Human Lead Libraries Link Longevity Lysine Malignant Neoplasms Molecular Biology Molecular Chaperones Mutation Nitrogen Nutrient Nutritional Pathway interactions Phosphotransferases Polymerase Process Proteins RNA Polymerase I RNA Polymerase II Recruitment Activity Regulation Regulatory Pathway Resistance Ribosomal DNA Role Saccharomycetales Screening procedure Signal Pathway Signal Transduction Sirolimus Source Time Yeast Model System base cancer risk cancer therapy cell growth chromatin immunoprecipitation chromatin modification detection of nutrient histone acetyltransferase inhibitor/antagonist mutant next generation novel programs promoter response yeast genetics

项目摘要

DESCRIPTION (provided by applicant): Precise control of cell growth and proliferation in response to nutrient availability is essential for human health. Aberrant regulation of nutrient sensing pathways, either through elevated nutrient availability or genetic mutation, can lead to inappropriate cell growth or proliferation and cause diseases such as cancer. One critical aspect of nutrient signaling is the regulation of a cell's gene expression program. How cells transmit nutrient information to the machinery regulating gene expression is still poorly understood, however. Because DNA is packaged into chromatin, which consists of DNA in a complex with histone proteins, nutrient signaling must regulate chromatin structure to elicit the epigenetic changes necessary to alter gene expression. The studies outlined in this proposal will make use of the budding yeast model system to understand how a critical nutrient signaling cascade, the target of rapamycin (TOR) pathway, regulates epigenetic processes to control gene transcription. Aim I of this project will utilize yeast genetic, molecular biology, and biochemical approaches to delineate how TOR signaling regulates a histone chaperone complex to control RNA polymerase I transcription of ribosomal DNA. Aim II will use a chemical genomics-based approach to find TOR-regulated epigenetic pathways by screening a histone H3 and H4 mutant library in the presence of the TOR inhibitor rapamycin. These mutants will then be combined with mutations in the TOR pathway to further characterize their genetic interactions. In combination, these studies will delineate a novel epigenetic pathway important for RNA polymerase I transcription and will serve to identify new, TOR-regulated epigenetic pathways critical for nutrient regulated cell growth. PUBLIC HEALTH RELEVANCE: The project's goal is to identify how cells transmit nutrient signals to the epigenetic machinery to regulate gene expression critical for cell growth. Because nutrient signaling pathways are aberrantly regulated in cancer, understanding how they control epigenetic processes will lead to the identification of new anti-cancer drug targets.

描述（由申请人提供）：根据营养物质的可用性精确控制细胞生长和增殖对于人类健康至关重要。营养感应途径的异常调节，无论是通过提高营养可用性还是基因突变，都可能导致细胞生长或增殖不当，并导致癌症等疾病。营养信号传导的一个关键方面是细胞基因表达程序的调节。然而，细胞如何将营养信息传递给调节基因表达的机制仍然知之甚少。由于 DNA 被包装到染色质中，而染色质由 DNA 与组蛋白的复合物组成，因此营养信号传导必须调节染色质结构，以引发改变基因表达所需的表观遗传变化。该提案中概述的研究将利用芽殖酵母模型系统来了解关键的营养信号级联（雷帕霉素（TOR）途径的目标）如何调节表观遗传过程以控制基因转录。该项目的目标 I 将利用酵母遗传学、分子生物学和生化方法来描述 TOR 信号传导如何调节组蛋白伴侣复合物以控制核糖体 DNA 的 RNA 聚合酶 I 转录。 Aim II 将使用基于化学基因组学的方法，通过在 TOR 抑制剂雷帕霉素存在的情况下筛选组蛋白 H3 和 H4 突变体库来寻找 TOR 调节的表观遗传途径。然后，这些突变体将与 TOR 通路中的突变相结合，以进一步表征它们的遗传相互作用。结合起来，这些研究将描绘出对 RNA 聚合酶 I 转录很重要的新表观遗传途径，并将有助于识别对营养调节细胞生长至关重要的新的 TOR 调节的表观遗传途径。公共健康相关性：该项目的目标是确定细胞如何将营养信号传递到表观遗传机制，以调节对细胞生长至关重要的基因表达。由于营养信号通路在癌症中受到异常调节，了解它们如何控制表观遗传过程将有助于识别新的抗癌药物靶点。