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Eukaryotic Cell doi:10.1128/EC.00070-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Genome-wide location analysis of Candida albicans Upc2p, a regulator of sterol metabolism and azole drug resistance

Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Québec, Canada; Université des Sciences et Technologies de Lille, Lille, France; Institut de recherches cliniques de Montréal, Montreal, Québec, Canada (Affiliated with Université de Montréal)

^* To whom correspondence should be addressed. Email: martine.raymond{at}umontreal.ca.

	Abstract

Upc2p, a transcription factor of the zinc cluster family, is an important regulator of sterol biosynthesis and azole drug resistance in Candida albicans. To better understand Upc2p function in C. albicans, we used genome-wide location profiling (ChIP-chip) to identify its transcriptional targets in vivo. A triple HA epitope, introduced at the C-terminus of Upc2p, conferred a gain-of-function effect to the fusion protein. Location profiling identified 202 bound promoters (P-value < 0.05). Over-represented functional groups of genes whose promoters were bound by Upc2p included 12 genes involved in ergosterol biosynthesis (NCP1, ERG11, ERG2, others), 18 genes encoding ribosomal subunits (RPS30, RPL32, RPL12, others), 3 genes encoding drug transporters (CDR1, MDR1, YOR1), 4 genes encoding transcription factors (INO2, ACE2, SUT1, UPC2) and 6 genes involved in sulfur amino acid metabolism (MET6, SAM2, SAH1, others). Bioinformatic analyses suggested that Upc2p binds to the DNA motif 5'-vnCGbdTr that includes the previously characterized Upc2p-binding site 5'-TCGTATA. Northern blot analysis showed that enriched binding correlates with increased expression for the analyzed Upc2p targets (ERG11, MDR1, CDR1, YOR1, SUT1, SMF12, CBP1). Analysis of ERG11, MDR1 and CDR1 transcripts in wild-type and upc2/upc2 strains grown under Upc2p activating conditions (lovastatin treatment and hypoxia) showed that Upc2p regulates its targets in a complex manner, acting as an activator or as a repressor depending upon the target and the activating condition. Taken together, our results indicate that Upc2p is a key regulator of ergosterol metabolism. They also suggest that Upc2p may contribute to azole resistance by regulating the expression of drug efflux pump-encoding genes in addition to ergosterol biosynthesis genes.

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