A phenotypic profile of the Candida albicans regulatory network.
A phenotypic profile of the Candida albicans regulatory network.
复制标题
DOI：
10.1371/journal.pgen.1000783
复制
发表时间：
2009-12
期刊：
影响因子：
4.5
通讯作者：
Johnson AD
中科院分区：
文献类型：
--
作者：
Homann OR;Dea J;Noble SM;Johnson AD
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。它最后一次与3亿多年前的模式酵母酿酒酵母有共同的祖先。我们描述了143个基因匹配的C.白色念珠菌，其中每一个已经删除了一个特定的转录调节因子。这个集合代表了非必需转录电路的很大一部分。使用55种生长条件的筛选开发每个突变体的表型谱。结果确定了许多个体转录调节因子的生物学作用;对于许多人来说，这项工作代表了对其功能的首次描述。例如，四分之一的菌株显示出改变的菌落形成，这是一种反映酵母、假菌丝和菌丝细胞形式之间转变的表型。这些转变与发病机制密切相关，已被广泛研究，但我们的工作几乎使已知影响它们的转录调节因子的数量增加了一倍。作为第二个例子，近四分之一的基因敲除菌株影响了对常用抗真菌药物的敏感性;尽管一些转录调节因子先前与对这些药物的敏感性有关，但我们的工作表明了许多其他的敏感性和耐药性机制。最后，我们的研究结果告诉我们转录网络是如何进化的。与现有的S。酿酒酵母数据（补充了额外的S.酿酒酵母实验报告这里）允许第一个系统的分析表型保守的正交转录调控在一个大的进化距离。我们发现，尽管这些物种之间记录了许多特定的布线变化，但orthopathic转录调控因子敲除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，即许多布线变化会影响电路的详细架构，但不会影响其整体输出。理解生物体生物学的一个关键目标是描述控制其基因表达的调控网络。基因表达的变化导致新的细胞表型，这些表型可以受到进化力量的作用，从而影响这些网络的配置。我们已经开发了一个表型描述的转录调控网络的主要真菌病原体的人类，白色念珠菌，通过单独删除编码转录调节因子的基因，并观察在各种环境条件下产生的表型。这种方法提供了深入了解许多以前未表征的监管机构的生物学作用，并允许我们分配组的监管机构特定的生物学作用，其中许多是相关的发病机制。例如，我们确定了影响抗真菌药物敏感性的调节剂组，获得铁的能力（人类宿主中生物体的挑战）以及形成复杂多细胞菌落的能力。我们的研究结果还使我们能够分析如何与转录调节因子的表型变化生物体分歧。与C. albicans与酵母S.酿酒酵母揭示了相关的转录调节因子之间的强表型保守性，尽管超过3亿年的物种分离。
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. A key goal in the understanding of the biology of an organism is the description of the regulatory networks that control the expression of its genes. Changes in gene expression result in new cellular phenotypes that can be acted upon by evolutionary forces to influence the configuration of these networks. We have developed a phenotypic description of the transcriptional regulatory networks of the major fungal pathogen of humans, Candida albicans, by individually deleting genes that encode transcriptional regulators and observing the resulting phenotypes in a variety of environmental conditions. This approach provides insight into the biological roles of many previously uncharacterized regulators, and allows us to assign groups of regulators to specific biological roles, many of which are relevant to pathogenesis. For example, we identified groups of regulators that influenced sensitivity to antifungal drugs, the ability to acquire iron (a challenge for organisms in a human host), and the ability to form complex multi-cellular colonies. Our results also allow us to analyze how the phenotypes associated with transcriptional regulators change as organisms diverge. A comparison of C. albicans data with that from the well-characterized yeast S. cerevisiae revealed strong phenotypic conservation between related transcriptional regulators, despite the more than 300 million years which separate the species.
登录
查看更多内容
影响因子：
56.9
作者：
Hillenmeyer, Maureen E.;Fung, Eula;Giaever, Guri
通讯作者：
Giaever, Guri
影响因子：
--
作者：
Baek, Yong-Un;Li, Mingchun;Davis, Dana A.
通讯作者：
Davis, Dana A.
影响因子：
64.8
作者：
Dujon, B;Sherman, D;Souciet, JL
通讯作者：
Souciet, JL
影响因子：
11.4
作者：
Bennett, RJ;Johnson, AD
通讯作者：
Johnson, AD
影响因子：
9.8
作者：
Gasch AP;Moses AM;Chiang DY;Fraser HB;Berardini M;Eisen MB
通讯作者：
Eisen MB