Department of Microbiology and Immunology, University of California San Francisco, San Francisco, California, USA.
PLoS Genet. 2009 Dec;5(12):e1000783. doi: 10.1371/journal.pgen.1000783. Epub 2009 Dec 24.
Candida albicans is a normal resident of the gastrointestinal tract and also the most prevalent fungal pathogen of humans. It last shared a common ancestor with the model yeast Saccharomyces cerevisiae over 300 million years ago. We describe a collection of 143 genetically matched strains of C. albicans, each of which has been deleted for a specific transcriptional regulator. This collection represents a large fraction of the non-essential transcription circuitry. A phenotypic profile for each mutant was developed using a screen of 55 growth conditions. The results identify the biological roles of many individual transcriptional regulators; for many, this work represents the first description of their functions. For example, a quarter of the strains showed altered colony formation, a phenotype reflecting transitions among yeast, pseudohyphal, and hyphal cell forms. These transitions, which have been closely linked to pathogenesis, have been extensively studied, yet our work nearly doubles the number of transcriptional regulators known to influence them. As a second example, nearly a quarter of the knockout strains affected sensitivity to commonly used antifungal drugs; although a few transcriptional regulators have previously been implicated in susceptibility to these drugs, our work indicates many additional mechanisms of sensitivity and resistance. Finally, our results inform how transcriptional networks evolve. Comparison with the existing S. cerevisiae data (supplemented by additional S. cerevisiae experiments reported here) allows the first systematic analysis of phenotypic conservation by orthologous transcriptional regulators over a large evolutionary distance. We find that, despite the many specific wiring changes documented between these species, the general phenotypes of orthologous transcriptional regulator knockouts are largely conserved. These observations support the idea that many wiring changes affect the detailed architecture of the circuit, but not its overall output.
白色念珠菌是胃肠道的正常居民，也是人类最常见的真菌病原体。它与模式酵母酿酒酵母在 3 亿多年前最后一次拥有共同的祖先。我们描述了一组 143 个遗传匹配的白色念珠菌菌株，每个菌株都被删除了特定的转录调节剂。该集合代表了非必需转录电路的很大一部分。使用 55 种生长条件的筛选对每个突变体进行了表型分析。结果确定了许多单个转录调节剂的生物学作用；对于许多人来说，这项工作代表了他们功能的首次描述。例如，四分之一的菌株显示出改变的菌落形成，这一表型反映了酵母、假菌丝和菌丝细胞形式之间的转变。这些与发病机制密切相关的转变已经得到了广泛的研究，但我们的工作几乎使影响它们的转录调节剂的数量增加了一倍。例如，近四分之一的敲除菌株对常用抗真菌药物的敏感性产生影响；尽管以前已经有几个转录调节剂被认为与这些药物的敏感性有关，但我们的工作表明还有许多其他的敏感性和耐药性机制。最后，我们的结果说明了转录网络是如何进化的。与现有的酿酒酵母数据（补充了这里报告的其他酿酒酵母实验）进行比较，允许首次在大进化距离上对同源转录调节剂的表型保守性进行系统分析。我们发现，尽管在这些物种之间记录了许多特定的布线变化，但同源转录调节剂敲除体的一般表型在很大程度上是保守的。这些观察结果支持了这样一种观点，即许多布线变化影响了电路的详细结构，但不影响其整体输出。
