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供应对人类健康至关重要。营养感应通路的异常调节，无论是通过提高营养可获得性，还是通过基因突变，都可能导致不适当的细胞生长或增殖，并导致癌症等疾病。营养信号的一个关键方面是调节细胞的基因表达程序。然而，细胞如何将营养信息传递到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DNA与组蛋白组成的复合体组成，营养信号必须调节染色质结构，才能引发改变基因表达所需的表观遗传变化。这项建议中概述的研究将利用发芽酵母模型系统来了解关键营养信号级联反应是如何调节表观遗传过程以控制基因转录的。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的方法来描述TOR信号如何调节组蛋白伴侣复合体来控制核糖体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，在TOR抑制剂雷帕霉素存在的情况下，通过筛选组蛋白H3和H4突变文库来寻找TOR调控的表观遗传途径。然后，这些突变体将与TOR途径中的突变结合，以进一步表征它们的遗传相互作用。结合起来，这些研究将描绘出一条对RNA聚合酶I转录重要的新的表观遗传途径，并将有助于识别新的、TOR调控的表观遗传途径，这些途径对营养调控的细胞生长至关重要。

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.