Abstract:The fungal pathogen Candida glabrata is an emerging cause of candidiasis in part owing to its robust ability to acquire tolerance to the major clinical antifungal drug fluconazole. Similar to the related species Candida albicans, C. glabrata most typically gains azole tolerance via transcriptional induction of a suite of resistance genes including an ABCG type ATP-binding cassette transporter referred to as CDR1 in Candida species. In C. glabrata, CDR1 expression is primarily controlled by the activity of a transcriptional activator protein called Pdr1. Strains exhibiting reduced azole susceptibility often contain substitution mutations in the PDR1 that in turn lead to elevated mRNA levels of target genes with associated azole resistance. Pdr1 activity is also induced upon loss of the mitochondrial genome status and upon challenge by azole drugs. While extensive analyses of the transcriptional effects of Pdr1 have identified a number of genes that are regulated by this factor, we cannot yet separate direct from indirect target genes. Here we use chromatin immunoprecipitation (ChIP) coupled with high throughput sequencing (ChIP-seq) to identify the promoters and associated genes directly regulated by Pdr1. These genes include many that are shared with the yeast Saccharomyces cerevisiae but others that are unique to C. glabrata including the ABC transporter-encoding locus YBT1, genes involved in DNA repair and several others. These data provide the outline for understanding the primary response genes involved in production of Pdr1-dependent azole resistance in C. glabrata.

Status: Published Type: Journal Article PubMed ID: 25199772

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#1-10(ATF2-CAGL0K09702g) #11-20(CDR1-PDR16) #21-27(PUP1-YOR1)

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