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: 10459436
• 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/10459436
• 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; gene regulatory network; 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分化的主要驱动因素。虽然这已被充分研究 发展，但其在非发展过程中的重要性却鲜为人知。整体愿景 该实验室的目标是全面表征基因调控网络（GRN）的进化重新布线 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 宿主的生存和毒力发生变化。实验室此前发现了显着差异 共生和机会性酵母病原体光滑念珠菌如何调节其磷酸盐 饥饿（PHO）反应与其非共生近亲酿酒酵母相比： 共生体在数量和功能上都显着扩展了其 PHO 响应目标，这 归因于其主转录因子（TF）的衍生变化，减少了对 联合特工。该实验室未来五年的目标是确定这种现象的遗传和机制基础 TF进化的新模式，即通过减少co-TF依赖性来获取新目标，以及 这种进化对磷酸盐饥饿的应激抵抗力以及宿主的组合应激。 了解该模型的压力反应如何自行演变以及与其他压力的相互作用 反应将开始阐明共生酵母中应激反应进化的原理 一般的。为了实现这一目标，将追求三个方向：1）阐明新模式的机制 使用生物物理和适应性测定研究 TF 进化及其对下游反应的影响； 2） 通过确定压力反应之间的串扰及其在共生酵母中的进化方式，剖析 C. glabrata 和 S. PHO 反应与氧化应激和一般应激反应的相互作用。 酿酒酵母； 3) 确定 PHO 网络在其他共生酵母和相关非酵母中如何进化 共生体，使用转录组分析与全基因组染色质 IP 相结合。研究建议 该应用具有创新性，因为进化方法将识别接线中的关键变化 宿主适应的应激反应 GRN 的研究。拟议的研究意义重大，因为它 都将阐明 GRN 演化的一般原则，并提供一个概念框架 开发针对应激反应的新型抗真菌策略。