The ability of Candida albicans, an important human fungal pathogen, to develop filamentous forms is a crucial determinant for host invasion and virulence. While hypoxia is one of the predominant host cues that promote C. albicans filamentous growth, the regulatory circuits that link oxygen availability to filamentation remain poorly characterized. We have undertaken a genetic screen and identified the two transcription factors Ahr1 and Tye7 as central regulators of the hypoxic filamentation. Both ahr1 and tye7 mutants exhibited a hyperfilamentous phenotype specifically under an oxygen-depleted environment suggesting that these transcription factors act as negative regulators of hypoxic filamentation. By combining microarray and ChIP-chip analyses, we have characterized the set of genes that are directly modulated by Ahr1 and Tye7. We found that both Ahr1 and Tye7 modulate a distinct set of genes and biological processes. Our genetic epistasis analysis supports our genomic finding and suggests that Ahr1 and Tye7 act independently to modulate hyphal growth in response to hypoxia. Furthermore, our genetic interaction experiments uncovered that Ahr1 and Tye7 repress the hypoxic filamentation via the Efg1 and Ras1/Cyr1 pathways, respectively. This study yielded a new and an unprecedented insight into the oxygen-sensitive regulatory circuit that control morphogenesis in a fungal pathogen.
Transcription factors play key roles in cellular regulation and are critical in the control of drug resistance in the fungal pathogen Candida albicans. We found that activation of the transcription factor C4_02500C_A (Adr1) conferred significant resistance against fluconazole. In Saccharomyces cerevisiae, Adr1 is a carbon-source-responsive zinc-finger transcription factor required for transcription of the glucose-repressed gene ADH1 and of genes required for ethanol, glycerol, and fatty acid utilization. Motif scanning of promoter elements suggests that Adr1 may be rewired in fungi and governs the ergosterol synthesis pathway in C. albicans. Because previous studies have identified the zinc-cluster transcription factor Upc2 as a regulator of the ergosterol pathway in both fungi, we examined the relationship of Adr1 and Upc2 in sterol biosynthesis in C. albicans. Phenotypic profiles of either ADR1 and UPC2 modulation in C. albicans showed differential growth in the presence of fluconazole; either adr1 or upc2 homozygous deletion results in sensitivity to the drug while their activation generates a fluconazole resistant strain. The rewiring from ergosterol synthesis to fatty acid metabolism involved all members of the Adr1 regulon except the alcohol dehydrogenase Adh1, which remains under Adr1 control in both circuits and may have been driven by the lifestyle of S. cerevisiae, which requires the ability to both tolerate and process high concentrations of ethanol.
Background: The ability of Candida albicans, an important human fungal pathogen, to develop filamentous forms is a crucial determinant for host invasion and virulence. Filamentation is triggered by different host environmental cues such as temperature and pH. Hypoxia, the dominant conditions that C. albicans encounters inside the human host, promote filamentation, however, the contributing mechanisms remain poorly characterized. Methods: We performed a quantitative analysis of gene deletion mutants from different collections of protein kinases and transcriptional regulators in C. albicans to identify specific modulators of the hypoxic filamentation. We used genome-wide transcriptional profiling (Microarrays) and promoter occupancy (ChIP-chip) to characterize regulons of two transcription factors that were associated with the hypoxic filamentation. Genetic interactions were also used to assess functional relationships among the newly identified modulators of hypoxic filamentation and the well-known C. albicans core morphogenetic regulators. Results: Our genetic screen uncovered two transcription factors, Ahr1 and Tye7, that act as prominent regulators of C. albicans filamentation specifically under hypoxia. Both ahr1 and tye7 mutants exhibited a hyperfilamentous phenotype specifically under an oxygen-depleted environment suggesting that these transcription factors act as a negative regulator of hypoxic filamentation. By combining microarray and ChIP-chip data, we have characterized the set of genes that are directly modulated by Ahr1 and Tye7. We found that both Ahr1 and Tye7 modulate a different set of genes and biological processes. Our genetic epistasis analysis supports our genomic finding and suggests that Ahr1 and Tye7 act independently to modulate hyphal growth in response to hypoxia. Furthermore, our genetic interaction experiments uncovered that Ahr1 and Tye7 repress the hypoxic filamentation growth via the Efg1 and Ras1/Cyr1 pathways, respectively. Conclusion: In sum, this investigation represents an informative resource toward the understanding of how hypoxia, the predominant condition inside the host, shapes the invasive filamentous growth of C. albicans.
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