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The molecular mechanism of white-opaque switching in Candida albicans.

机译:白色念珠菌白色不透明转换的分子机理。

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摘要

White-opaque switching is a process by which the opportunistic fungal pathogen Candida albicans reversibly alternates between two growth states, named "white" and "opaque". The white-opaque switch regulates over 400 genes transcriptionally, and cells in each state have different morphology, virulence properties, metabolism, and mating competency. At the time I started my work, there was minimal molecular understanding of the white-opaque switch, and my goal was to identify the genes responsible for generating the opaque state. My work identified a gene, which we named White-Opaque Regulator 1 (WOR1), as the master regulator of the white-opaque switch. This gene is necessary for opaque formation and ectopic expression of WOR1 can drive cells to the opaque state, as verified through an examination of morphology, expression profiling, and behavioral tests. Northern analysis and chromatin immunoprecipitation (ChIP) assays revealed that Wor1 binds its own promoter and upregulates its own expression, forming a self-sustaining positive feedback loop.;Subsequent work sought to understand Wor1 in the context of other transcriptional regulators with known effects on white-opaque switching (CZF1, EFG1 , and WOR2). Mutants of CZF1, EFG1, and WOR2 were analyzed in combination with WOR1 to define genetic epistasis relationships. This genetic analysis was combined with ChIP experiments to analyze where Wor1 was associated with chromatin across the entire C. albicans genome. Wor1 was found to associate with the DNA upstream of each of the other regulators. Using the genetic relationships and ChIP data together, we defined a "circuit" of interlocking regulatory feedback loops that are modeled to reinforce Wor1 expression during initiation of the switch to the opaque state.;Unpublished work found that increased osmotic pressure or contact with solid surfaces can increase the frequency of white-to-opaque switching. Ongoing research focuses on purifying Wor1 for use in assays to determine if it can directly bind DNA. Together these studies enriched our understanding of the molecular control of the white-opaque switch.
机译:白不透明转换是一个过程,机会性真菌病原体白色念珠菌可逆地在两个生长状态之间交替变化,称为“白”和“不透明”。不透明的白色开关可转录调节400多个基因,每种状态下的细胞具有不同的形态,毒力特性,代谢和交配能力。在我开始工作时,对白色不透明开关的分子了解极少,我的目标是确定引起不透明状态的基因。我的工作确定了一个基因,我们将其命名为白不透明调节剂1(WOR1),作为白不透明开关的主调节剂。该基因对于不透明的形成是必不可少的,并且WOR1的异位表达可以驱动细胞进入不透明状态,这已通过形态检查,表达谱分析和行为测试得到了证实。 Northern分析和染色质免疫沉淀(ChIP)分析显示,Wor1结合其自身的启动子并上调其表达,形成了一个自我维持的正反馈回路。;随后的工作试图在其他对白蛋白有已知作用的转录调节子的背景下了解Wor1不透明切换(CZF1,EFG1和WOR2)。将CZF1,EFG1和WOR2的突变体与WOR1结合进行分析以定义遗传上位关系。该遗传分析与ChIP实验相结合,可分析整个白色念珠菌基因组中Wor1与染色质相关的位置。发现Wor1与每个其他调节子上游的DNA相关。结合遗传关系和ChIP数据,我们定义了一个互锁的调节反馈回路的“回路”,该回路被建模为在转换到不透明状态的过程中增强Wor1的表达。会增加白色到不透明切换的频率。正在进行的研究集中在纯化Wor1以用于测定以确定它是否可以直接结合DNA。这些研究共同丰富了我们对白不透明开关的分子控制的理解。

著录项

  • 作者

    Zordan, Rebecca E.;

  • 作者单位

    University of California, San Francisco.;

  • 授予单位 University of California, San Francisco.;
  • 学科 Biology Molecular.;Biology Genetics.
  • 学位 Ph.D.
  • 年度 2008
  • 页码 189 p.
  • 总页数 189
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;遗传学;
  • 关键词

  • 入库时间 2022-08-17 11:38:58

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