Abstract
Biofilm formation by Candida albicans is a key aspect of its pathobiology and is regulated by an integrated network of transcription factors (Bcr1, Brg1, Efg1, Ndt80, Rob1, and Tec1). To understand the details of how the transcription factors function together to regulate biofilm formation, we used a systematic genetic interaction approach based on generating all possible double heterozygous mutants of the network genes and quantitatively analyzing the genetic interactions between them. Overall, the network is highly susceptible to genetic perturbation with the six network heterozygous mutants all showing alterations in biofilm formation (haploinsufficiency). In addition, many double heterozygous mutants are as severely affected as homozygous deletions. As a result, the network shows properties of a highly interdependent ‘small-world’ network that is highly efficient but not robust. In addition, these genetic interaction data indicate that TEC1 represents a network component whose expression is highly sensitive to small perturbations in the function of other networks TFs. We have also found that expression of ROB1 is dependent on both auto-regulation and cooperative interactions with other network TFs. Finally, the heterozygous NDT80 deletion mutant is hyperfilamentous under both biofilm and hyphae-inducing conditions in a TEC1-dependent manner. Taken together, genetic interaction analysis of this network has provided new insights into the functions of individual TFs as well as into the role of the overall network topology in its function.
Highlights
Candida albicans is a fungal commensal of the human gastrointestinal tract with the potential to cause both superficial mucosal and life-threatening invasive infections [1]
As one of the most important human fungal pathogens, C. albicans has been the subject of intensive study and, this work has informed our understanding of C. albicans pathobiology as well as fundamental paradigms of fungal infection biology [2]
Application of traditional genetic epistasis experiments to C. albicans requires the generation of double homozygous deletion mutant strains which is quite cumbersome, recent developments in the application of CRISPR-Cas9 are likely to improve this process [9, 10]
Summary
Candida albicans is a fungal commensal of the human gastrointestinal tract with the potential to cause both superficial mucosal and life-threatening invasive infections [1]. As one of the most important human fungal pathogens, C. albicans has been the subject of intensive study and, this work has informed our understanding of C. albicans pathobiology as well as fundamental paradigms of fungal infection biology [2] This progress has been due, in large part, to the development and refinement of genetic tools applicable to C. albicans over the last twenty years [3]. Large-scale genetic epistasis analysis was pioneered in the model organism Saccharomyces cerevisiae and has been extended to other organisms as well [5] This powerful genetics approach allows the development of functional models and networks that inform our understanding of complex multi-genic phenotypes and processes [6]. Double homozygous deletion mutants have been used sporadically in the study of C. albicans and no systematic epistasis analysis using double homozygous mutants has been undertaken, to our knowledge
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