EC Accepts, published online ahead of print on 19 June 2009

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Eukaryotic Cell doi:10.1128/EC.00074-09
Copyright (c) 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Role of Ndt80p in sterol metabolism regulation and azole resistance in Candida albicans

Adnane Sellam, Faïza Tebbji, and André Nantel^*

Biotechnology Research Institute, National Research Council of Canada, Montréal, Québec, H4P 2R2, Canada; Department of Anatomy and Cell Biology, McGill University, Montréal, Québec, H3A 1B1, Canada; Institut de recherche en biologie végétale, Université de Montréal, Montréal, Québec, H1X 2B2, Canada

^* To whom correspondence should be addressed. Email: andre.nantel{at}nrc-cnrc.gc.ca.

The Ndt80p transcription factor modulates azole tolerance in Candida albicans by controlling the expression of the gene for the drug efflux pump Cdr1p. To date, the contribution of this transcriptional modulator to drug tolerance are not yet well understood. Here we investigate the role of Ndt80p in mediating fluconazole tolerance by determining its genome-wide occupancy using Chromatin Immuno-Precipitation coupled to high-density tiling arrays. Ndt80p was found to bind a large number of gene promoters with diverse biological functions. Gene ontology analysis of these Ndt80p targets revealed a significant enrichment in gene products related to cell wall, carbohydrate metabolism, stress responses, hyphal development, multidrug transport and cell cycle. Ndt80p was found on the promoters of ergosterol biosynthesis genes including the azole target Erg11p. Additionally, expression profiling was used to identify fluconazole responsive-genes that require Ndt80p for their proper expression. We found that Ndt80p is crucial for the expression of numerous fluconazole-responsive genes, especially genes involved in ergosterol metabolism. Therefore, by combining genome-wide location and transcriptional profiling, we have characterized the Ndt80p fluconazole-dependent regulon and demonstrated the key role of this global transcriptional regulator in modulating sterol metabolism and drug resistance in C. albicans.