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Eukaryotic Cell, November 2007, p. 2122-2138, Vol. 6, No. 11
1535-9778/07/$08.00+0     doi:10.1128/EC.00327-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Genome-Wide Expression and Location Analyses of the Candida albicans Tac1p Regulon{triangledown} ,{dagger}

Teresa T. Liu,1,2,§ Sadri Znaidi,3,§ Katherine S. Barker,1,2 Lijing Xu,4 Ramin Homayouni,4,5 Saloua Saidane,3 Joachim Morschhäuser,6 André Nantel,7 Martine Raymond,3,8,{ddagger}* and P. David Rogers1,2,{ddagger}*

Departments of Clinical Pharmacy, Pharmaceutical Sciences, Molecular Sciences, and Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee, 38163,1 Children's Foundation Research Center of Memphis, Le Bonheur Children's Medical Center, Memphis, Tennessee 38103,2 Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, Quebec, Canada H3T 1J4,3 Bioinformatics Program, University of Memphis, Memphis, Tennessee 38152,4 Department of Biology, University of Memphis, Memphis, Tennessee 38152,5 Institut für Molekulare Infektionsbiologie, Universität Würzburg, Röntgenring 11, D-97070 Würzburg, Germany,6 Biotechnology Research Institute, National Research Council of Canada, Montréal, Quebec, Canada H4P 2R2,7 Department of Biochemistry, Université de Montréal, Montréal, Quebec, Canada H3T 1J48

Received 31 August 2007/ Accepted 16 September 2007

A major mechanism of azole resistance in Candida albicans is overexpression of the genes encoding the ATP binding cassette transporters Cdr1p and Cdr2p due to gain-of-function mutations in Tac1p, a transcription factor of the zinc cluster family. To identify the Tac1p regulon, we analyzed four matched sets of clinical isolates representing the development of CDR1- and CDR2-mediated azole resistance by using gene expression profiling. We identified 31 genes that were consistently up-regulated with CDR1 and CDR2, including TAC1 itself, and 12 consistently down-regulated genes. When a resistant strain deleted for TAC1 was examined similarly, expression of almost all of these genes returned to levels similar to those in the matched azole-susceptible isolate. Using genome-wide location (ChIP-chip) analysis (a procedure combining chromatin immunoprecipitation with hybridization to DNA intergenic microarrays), we found 37 genes whose promoters were bound by Tac1p in vivo, including CDR1 and CDR2. Sequence analysis identified nine new genes whose promoters contain the previously reported Tac1p drug-responsive element (CGGN4CGG), including TAC1. In total, there were eight genes whose expression was modulated in the four azole-resistant clinical isolates in a TAC1-dependent manner and whose promoters were bound by Tac1p, qualifying them as direct Tac1p targets: CDR1, CDR2, GPX1 (putative glutathione peroxidase), LCB4 (putative sphingosine kinase), RTA3 (putative phospholipid flippase), and orf19.1887 (putative lipase), as well as IFU5 and orf19.4898 of unknown function. Our results show that Tac1p binds under nonactivating conditions to the promoters of its targets, including to its own promoter. They also suggest roles for Tac1p in regulating lipid metabolism (mobilization and trafficking) and oxidative stress response in C. albicans.

* Corresponding author. Mailing address for P. David Rogers: Le Bonheur Children's Medical Center, Room 304 West Patient Tower, Children's Foundation Research Center, 50 North Dunlap Street, Memphis, TN 38103. Phone: (901) 287-5387. Fax: (901) 287-5036. E-mail: drogers{at}utmem.edu. Mailing address for Martine Raymond: Institute for Research in Immunology and Cancer, Université de Montréal, P.O. Box 6128, Station Centre-Ville, Montréal, Quebec, Canada H3C 3J7. Phone: (514) 343-6746. Fax: (514) 343-6843. E-mail: martine.raymond{at}umontreal.ca

{triangledown} Published ahead of print on 28 September 2007.

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

§ These two authors contributed equally to this work.

{ddagger} These two authors share senior authorship of this paper.

Eukaryotic Cell, November 2007, p. 2122-2138, Vol. 6, No. 11
1535-9778/07/$08.00+0     doi:10.1128/EC.00327-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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