Evolution of Stress Response Gene Regulatory Network in a Commensal and Opportunistic Yeast Pathogen

共生和机会性酵母病原体中应激反应基因调控网络的进化

• 批准号: 10227186
• 负责人: Bin Z He
• 金额: $ 37.71万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10227186
• 关键词: Antifungal Agents; Basic Science; Biological Assay; Biological Process; Biophysics; Candida; Candida glabrata; Chromatin; Coupled; Dependence; Development; Evolution; Foundations; Future; Genetic; Goals; Knowledge; Light; Mission; Modeling; National Institute of General Medical Sciences; Opportunistic Infections; Oxidative Stress; Phenotype; Public Health; Regulator Genes; Research; Resistance; Saccharomyces cerevisiae; Starvation; Stress; Virulence; Vision; Yeasts; base; biological adaptation to stress; combinatorial; fitness; genome-wide; innovation; inorganic phosphate; novel; opportunistic pathogen; pathogen; pathogenic fungus; response; transcription factor; transcriptome

Gene regulatory evolution is a major driver for phenotypic divergence. While this has been well-studied in development, its importance in non-developmental processes is far less understood. The overall vision of the lab is to fully characterize the evolutionary rewiring of gene regulatory networks (GRNs) for major stress responses in opportunistic yeast pathogens, and elucidate the contribution of such changes to the survival and virulence in the host. The lab previously discovered a significant difference in how a commensal and opportunistic yeast pathogen, Candida glabrata, regulates its Phosphate Starvation (PHO) response compared with its non-commensal relative, Saccharomyces cerevisiae: the commensal has dramatically expanded its PHO response targets both in number and in function, which was attributed to derived changes in its master transcription factor (TF) by being less dependent on the co-TF. The goal of the lab in the next five years is to determine the genetic and mechanistic bases of this novel mode of TF evolution, i.e. acquiring new targets by reducing co-TF dependence, and the effect of such evolution on stress resistance to phosphate starvation as well as combinatorial stresses in the host. Understanding how this model stress response evolved by itself and in its interaction with other stress responses will begin to elucidate the principles for stress response evolution in commensal yeasts in general. To reach this goal, three Directions will be pursued: 1) Elucidate the mechanisms of a novel mode of TF evolution and its impact on the downstream response, using biophysical and fitness assays; 2) Dissect the crosstalk between stress responses and how it evolved in commensal yeasts, by determining the interaction of PHO response with oxidative stress and general stress responses in C. glabrata and S. cerevisiae; 3) Determine how the PHO network evolved in other commensal yeasts and related non- commensals, using transcriptome profiling coupled with genome-wide Chromatin-IP. Research proposed in this application is innovative because the evolutionary approach will identify key changes in the wiring of the stress response GRNs underlying host adaptation. The proposed research is significant because it will both shed light on the general principles for GRN evolution, and will provide a conceptual framework for developing novel antifungal strategies targeting stress responses.

基因调控进化是表型差异的主要驱动因素。虽然这一点已经在 关于发展问题，人们对其在非发展进程中的重要性知之甚少。总体愿景 该实验室的目的是全面描述基因调控网络(GRN)的进化重组 机会性酵母病原体的主要应激反应，并阐明这些应激反应的贡献 改变寄主的存活率和致病力。该实验室之前发现了一个显著的差异 一种共生和机会性的酵母病原菌光滑假丝酵母如何调节其磷酸盐 饥饿(Pho)反应与其非共生近亲酿酒酵母的比较： Commensal在数量和功能上都极大地扩大了其pho响应目标，这 归因于其主要转录因子(Tf)的衍生变化，即较少依赖于 联合特遣部队。该实验室在未来五年的目标是确定这一现象的遗传和机制基础 转移因子进化的新模式，即通过减少共转移因子依赖来获得新的靶点，以及 这样的进化在胁迫对磷饥饿的抗性以及寄主的组合胁迫上都是如此。 了解该模型应激反应本身以及在与其他应激的相互作用中是如何演变的 响应将开始阐明在共生酵母中应激反应进化的原理 将军。为了实现这一目标，将从三个方面进行探索：1)阐明一种新模式的机制 使用生物物理和适合度分析，对转铁蛋白的进化及其对下游反应的影响；2) 通过确定压力反应和压力如何在共生酵母中进化之间的串扰，来剖析 光肩星天牛和光肩星天牛的pho反应与氧化胁迫和一般胁迫反应的交互作用。 酿酒酵母；3)确定pho网络如何在其他共生酵母和相关的非共生酵母中进化。 共集，使用转录组图谱与全基因组染色质IP相结合。建议进行的研究 这一应用是创新的，因为进化方法将识别布线中的关键变化 作为寄主适应基础的应激反应GRN。这项拟议的研究意义重大，因为它 两者都将阐明GRN进化的一般原则，并将提供一个概念性框架 用于开发针对应激反应的新型抗真菌策略。