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Expression profilling of C. glabrata response to fluconazole and the role of the transcription factor Rpn4 in such response

ABSTRACT: The goals of this study are to compare C. glabrata transcriptome profiling (RNA-seq) upon exposure to the antifungal fluconazole in order to assess antifungal response. The role of the transcription factor Rpn4 is clarified through comparison of the transcrptome profiles of WT and Rpn4 mutant cells. mRNA profiles of WT and ∆rpn4 were generated by deep sequencing, in duplicate, using Illumina HiSeq. The sequence reads that passed quality filters were analyzed with TopHat followed by HTSeq. RNA-seq data allowed to identify genes whose expression is regulated by the Rpn4 transcription factor (80 positively regulated and 212 negatively regulated) with a log2fold change ≥0.5 and p value <0.05. The transcriptomics data was then used to guide further work to detail the function of Rpn4.

ORGANISM(S): Nakaseomyces glabratus

PROVIDER: GSE129349 | GEO | 2019/09/27

REPOSITORIES: GEO

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Project description:Azole antifungal agents such as fluconazole exhibit fungistatic activity against Candida albicans. Strategies to enhance azole antifungal activity would be therapeutically appealing. In an effort to identify transcriptional pathways that influence fluconazole susceptibility, we sought to identify transcription factors (TFs) involved in this process. From a collection of C. albicans strains disrupted for genes encoding TFs (Homann et al., PLoS Genet. 2009;5:e1000783), four exhibited a marked reduction in minimum fungicidal concentration (MFC) in both RPMI and YPD media. One of these, UPC2, has been previously characterized with regard to its role in azole susceptibility. Of mutants representing the three remaining TF genes of interest, one (CAS5) was unable to recover from fluconazole exposure at concentrations as low as 2 M-BM-5g/mL after 72 hours in YPD medium. This mutant also showed reduced susceptibility and a clear zone of inhibition by Etest, was unable to grow on solid media containing 10 M-BM-5g/mL fluconazole, and exhibited increased susceptibility by time-kill analysis. CAS5 disruption in highly azole-resistant clinical isolates exhibiting multiple resistance mechanisms did not alter susceptibility. However, CAS5 disruption in strains with specific resistance mutations in ergosterol biosynthesis or efflux pumps resulted in a moderate reduction in MIC and MFC. Genome-wide transcriptional analysis was performed in the presence of fluconazole and was consistent with the suggested role of CAS5 in cell wall organization while also suggesting a role in iron transport and homeostasis. These findings suggest that Cas5 regulates a transcriptional network that influences susceptibility of C. albicans to fluconazole. Further delineation of this transcriptional network may identify targets for potential co-therapeutic strategies to enhance the activity to the azole class of antifungals. We examined the genome-wide gene expression profiles of the wild-type parent strain SC5314 and its cas5M-NM-^T/M-NM-^T derivative in response to fluconazole in order to identify genes whose expression in response to fluconazole is influenced by Cas5.

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Expression profilling of C. glabrata response to fluconazole and the role of the transcription factor Rpn4 in such response

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