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Eukaryotic Cell, May 2008, p. 836-847, Vol. 7, No. 5
1535-9778/08/$08.00+0     doi:10.1128/EC.00070-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Genomewide Location Analysis of Candida albicans Upc2p, a Regulator of Sterol Metabolism and Azole Drug Resistance ^,

Sadri Znaidi,¹ Sandra Weber,¹ Osman Zin Al-Abdin,¹ Perrine Bomme,^1,2 Saloua Saidane,¹ Simon Drouin,³ Sébastien Lemieux,¹ Xavier De Deken,^1, François Robert,³ and Martine Raymond^1*

Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Québec, Canada,¹ Université des Sciences et Technologies de Lille, Lille, France,² Institut de Recherches Cliniques de Montréal (affiliated with Université de Montréal), Montreal, Québec, Canada³

Received 21 February 2008/ Accepted 24 March 2008

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 genomewide location profiling to identify the transcriptional targets of Upc2p in vivo. A triple hemagglutinin epitope, introduced at the C terminus of Upc2p, conferred a gain-of-function effect on the fusion protein. Location profiling identified 202 bound promoters (P < 0.05). Overrepresented functional groups of genes whose promoters were bound by Upc2p included 12 genes involved in ergosterol biosynthesis (NCP1, ERG11, ERG2, and others), 18 genes encoding ribosomal subunits (RPS30, RPL32, RPL12, and others), 3 genes encoding drug transporters (CDR1, MDR1, and YOR1), 4 genes encoding transcription factors (INO2, ACE2, SUT1, and UPC2), and 6 genes involved in sulfur amino acid metabolism (MET6, SAM2, SAH1, and 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 increased binding correlates with increased expression for the analyzed Upc2p targets (ERG11, MDR1, CDR1, YOR1, SUT1, SMF12, and CBP1). The 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.

Published ahead of print on 4 April 2008.

Supplemental material for this article may be found at http://ec.asm.org/.

Present address: IRIBHM, ULB, Campus Erasme, Brussels, Belgium.