Epigenetic regulation by TOR signaling

描述（由申请人提供）：精确控制细胞生长和增殖以响应营养可用性对人类健康至关重要。营养感应途径的异常调节，无论是通过提高营养可用性或基因突变，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，染色质由与组蛋白复合的DNA组成，营养信号必须调节染色质结构，以引起改变基因表达所必需的表观遗传变化。本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）通路的靶标）如何调节表观遗传过程以控制基因转录。本项目的目的I将利用酵母遗传学、分子生物学和生物化学方法来描述TOR信号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。目的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。然后将这些突变体与TOR途径中的突变组合，以进一步表征它们的遗传相互作用。结合起来，这些研究将描绘一个新的表观遗传途径重要的RNA聚合酶I转录，并将有助于确定新的，TOR调节的表观遗传途径的营养调控细胞生长的关键。

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.