Abstract
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.
Highlights
The transcriptional networks that orchestrate gene expression are complex
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
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
Summary
Even in single-celled organisms, these networks must specify different cell types, must coordinate responses to different external cues, and must maintain homeostasis in a constantly changing environment The evolution of such networks occurs by numerous mechanisms, including gains, losses, and modifications of transcriptional regulators and the DNA sequences they recognize (cis-regulatory sequences). We broadly explore transcription networks in Candida albicans, the most prevalent fungal pathogen of humans, and compare them to those in S. cerevisiae These two organisms last shared a common ancestor some 300–900 million years ago [1,2], and, in terms of coding sequences, their genomes are approximately as divergent as those of fish and humans [3]. A smaller library of TRKOs has been constructed in C. albicans [7], extensive phenotyping has not been reported, as the library was designed primarily for preliminary genetic screens
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