PROJECT 4: ENVIRONMENT-GENOME INTERACTIONS

项目4--摘要 环境-基因组相互作用 基因组和它编码的分子电路并不是单独作用的，而是嵌入到一个相互作用的网络中 有环境因素和刺激，如营养素、激素、药物、毒素和其他化学物质 化合物。在这个项目中，我们将应用多方面的方法来系统地研究相互作用 有机体和环境之间的关系，目的是开发基因-环境的大型地图 交互并分析这些映射，以利用交互的基本原则和规则 用于预测性的。我们将使用两种互补的网络映射方法，一种基于排序 另一种是基于高密度化学发生筛选平台的。 该项目有三个具体目标。目标1是基于保护性突变模式的原理 在基因组中获得的，当基因组暴露在有毒的小分子生长抑制物中时，可能会 用于同时探索蛋白质之间的相互作用和研究生物体的基因组如何相互作用 在这样的环境下。我们没有使用代表整个基因组的基因敲除菌株系统，而是 将允许基因组在接触小分子时发生适应性变化，然后对其进行分析 系统地。在这项测试中，共有60种药物将在酵母中进行测试。然后，这些研究将反映在 单倍体人类细胞系，对人类细胞如何进行小规模全基因组测序研究 远离抗癌药物的突变。AIM 2将采用互补遗传作图方法来进一步 开发能够抵抗环境干扰的基因网络。利用一种 新的高通量6144菌落筛选格式，我们将筛选包含125种化合物的文库 单倍体酿酒酵母菌株高表达或低表达完整基因，模拟结构 暴露在环境毒素下的基因组发生的变化。然后，我们将测试以下内容的子集 人类癌细胞中同源基因之间的相互作用空间。在第三个目标中，我们建议整合 来自进化抗性(AIM 1)和全基因组的化学-遗传相互作用图谱 拥有大量先验知识的图书馆(目标2)，以建立跨物种的药物基因模型 互动。这个模型的目标将是学习如何从不同的角度预测人类药物-基因相互作用。 信息包括另一个物种的药物-基因相互作用的图谱。 总的来说，这些目标将极大地促进我们对全球基因网络的了解 控制细胞如何对药物产生抗药性。这些努力由系统中的两个先驱共同领导 传染病生物学：伊丽莎白·温泽勒博士，正式加入SDCSB教职员工 更新，以及现任SDCSB调查员Sumit Chanda博士。该项目利用酵母基因 Trey Ideker博士建立的筛查平台和计算分析专业知识，以及 两名SDCSB初级调查人员Hannah Carter博士和Jason Kreisberg博士的参与。

PROJECT 4 – SUMMARY ENVIRONMENT-GENOME INTERACTIONS The genome and molecular circuitry it encodes do not act alone, but are embedded in a web of interactions with environmental factors and stimuli such as nutrients, hormones, drugs, toxins and other chemical compounds. In this project, we will apply a multifaceted approach to systematically study the interactions between the organism and the environment, with the aim of developing large maps of gene-environment interactions and analyzing these maps to exploit fundamental principles and rules of interaction that can be used predictively. We will use two complementary network mapping approaches, one based on sequencing of resistant isolates and another based on a high-density chemogenetic screening platform. The project has three Specific Aims. Aim 1 is based on the principle that patterns of protective mutations acquired within a genome, when the genome is exposed to a toxic small molecule growth inhibitor, can be used to simultaneously explore protein-protein interactions and study how the organism's genome interacts with this environment. Instead of using a system of knockout strains that represent the entire genome, we will allow the genome to adaptively change when exposed to a small molecule and then analyze it systematically. A total of 60 drugs will be tested in yeast in this assay. These studies will then be mirrored in a haploid human cell line, to perform small-scale whole genome sequencing studies of how human cells mutate away from cancer drugs. Aim 2 will employ a complementary genetic mapping approach to further develop networks of genes that provide resistance to environmental perturbagens. Taking advantage of a new high-throughput 6144 colony screening format, we will screen a library of 125 chemical compounds in haploid S. cerevisiae strains that over-express or under-express complete genes, modeling the structural changes that develop in genomes exposed to environmental toxins. We will then test a subset of this interaction space among orthologous genes in human cancer cells. In the third aim, we propose to integrate the chemical-genetic interaction maps derived from evolutionary resistance (Aim 1) and genome-wide libraries (Aim 2) with a vast assortment of prior knowledge to build a cross-species model of drug-gene interaction. The goal of this model will be to learn how to predict human drug-gene interactions from diverse information including maps of drug-gene interactions in another species. Collectively, these aims will significantly advance our knowledge of the global gene networks that govern how cells become resistant to drugs. These efforts are led jointly by two pioneers in the systems biology of infectious disease: Dr. Elizabeth Winzeler, who formally joins the SDCSB faculty as of this renewal, and Dr. Sumit Chanda, a current SDCSB investigator. The project leverages the yeast genetic screening platform and computational analysis expertise established by Dr. Trey Ideker, as well as involvement from two SDCSB junior investigators, Dr. Hannah Carter and Dr. Jason Kreisberg.