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

Znaidi, Sadri; Weber, Sandra; Zin Al-Abdin, Osman; Bomme, Perrine; Saidane, Saloua; Drouin, Simon; Lemieux, Sébastien; De Deken, Xavier; Robert, François; Raymond, Martine

doi:10.1128/ec.00070-08

Cited by 119Fungal and yeast genetics researchAntifungal resistance and susceptibilityGenomics and Chromatin Dynamics

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

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Znaidi, Sadri, Weber, Sandra, Zin Al-Abdin, Osman, Bomme, Perrine, Saidane, Saloua, Drouin, Simon, Lemieux, Sébastien, De Deken, Xavier +2 more·2008·Eukaryotic Cell

DOI 10.1128/ec.00070-08PMC PMC2394978

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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 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 Δ/ upc2 Δ 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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Addition of a 3 HA tag to the C-terminal domain of zinc cluster transcription factors is efficient for their artificial activation in C. albicans and C. auris.
“The addition of a 3 HA tag to the C-terminal domain of zinc cluster transcription factors was shown to be efficient for their artificial activation in C. albicans and C. auris, presumably by relieving an activation domain from repression by an inhibitory domain (32–35).”
From Ume6-dependent pathways of morphogenesis and biofilm formation in Candida auris (2024) · cites this paper as [35]
Upc2 is thought to autoregulate and has been shown to bind its own promoter in experiments using chromatin immunoprecipitation with microarray technology (ChIP-chip).
“Interestingly, UPC2 wasnotfoundtobeupregulated in any of the four strains analyzed by microarray analysis, although Upc2 is thought to autoregulate and has been shown to bind its own promoter in experiments using chromatin immunoprecipitation with microarray technology (ChIP-chip) (33).”
From Gain-of-Function Mutations in UPC2 Are a Frequent Cause of ERG11 Upregulation in Azole-Resistant Clinical Isolates of Candida albicans (2012) · cites this paper as [33]
Upc2 has previously been shown to bind to the promoter of the drug efflux pump MDR1 but was not a cause of Mdr1-mediated drug resistance.
“Upc2 has previously been shown to bind to the promoter of the drug efflux pump MDR1 but was not a cause of Mdr1-mediated drug resistance (28, 33).”
From Gain-of-Function Mutations in UPC2 Are a Frequent Cause of ERG11 Upregulation in Azole-Resistant Clinical Isolates of Candida albicans (2012) · cites this paper as [33]
UPC2 induction does not increase significantly with escalating FS concentrations (factor 1.69 +/− 0.24 at 20 μM) and thus cannot explain an adaptive response at intermediate concentrations.
“However, UPC2 induction does not increase significantly with escalating FS concentrations (factor 1.69 +/− 0.24 at 20 μM) and can thus not explain an adaptive response at intermediate concentrations.”
From Inhibition ofCandida albicansby Fluvastatin Is Dependent on pH (2009) · cites this paper as [10]
Induction of UPC2 is detectable at low FS concentrations (factor 1.53 +/− 0.28 at 0.5 μM), indicating that FS has a physiological effect in this range.
“Induction of the major steroid synthesis regulator UPC2 [10], as determined by qPCR, is detectable at low FS concentrations (factor 1.53 +/− 0.28 at 0.5 μM), indicating that FS indeed has a physiological effect in this range.”
From Inhibition ofCandida albicansby Fluvastatin Is Dependent on pH (2009) · cites this paper as [10]

If a certain level of inhibition is exceeded, the cell might respond by inducing the activity of the steroid synthesis pathway, apparently by a UPC2-independent mechanism.
“If a certain level of inhibition is exceeded, the cell might respond by inducing the activity of the steroid synthesis pathway [10, 13], apparently by a UPC2-independent mechanism.”
From Inhibition ofCandida albicansby Fluvastatin Is Dependent on pH (2009) · cites this paper as [10]
A ChIP-chip experiment found that C. albicans Upc2 associates with the CDR1 gene.
“A ChIP-chip experiment was carried out on C. albicans Upc2 and this factor was found to associate with the CDR1 gene in this species [39].”
From The Candida glabrata Upc2A transcription factor is a global regulator of antifungal drug resistance pathways (2021) · cites this paper as [39]
Through genome-wide gene expression profiling, several ergosterol biosynthesis genes, including ERG11, were determined to be coordinately up-regulated with UPC2 in fluconazole-resistant isolates.
“Through genome-wide gene expression profiling, several ergosterol biosynthesis genes, including ERG11, were determined to be coordinately up-regulated with UPC2 in fluconazole-resistant isolates”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungusCandida albicans (2020) · cites this paper as [110]
ChIP-microarray location analysis identified 202 promoters bound by Upc2, including not only ergosterol biosynthesis genes (NCP1, ERG11, ERG1, ERG2, ERG24, ERG4, ERG5, ERG6, ERG9, ERG10, ERG25, ERG251 and UPC2) but also other transcription factors and the drug transporter genes CDR1 and MDR1.
“and ChIP-microarray location analysis identified 202 promoters bound by Upc2, including not only ergosterol biosynthesis genes (NCP1, ERG11, ERG1, ERG2, ERG24, ERG4, ERG5, ERG6, ERG9, ERG10, ERG25, ERG251 and UPC2) but also other transcription factors and the drug transporter genes CDR1 and MDR1.109–111”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungusCandida albicans (2020) · cites this paper as [110]
Upc2 has a regulatory role in more than just sterol biosynthesis genes.
“Upc2, however, was also shown to have a regulatory role in more than just sterol biosynthesis genes.”
From Molecular and genetic basis of azole antifungal resistance in the opportunistic pathogenic fungusCandida albicans (2020) · cites this paper as [110]

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Azole resistance is mediated by integration of sterol gene regulation and membrane transporter production by the zinc cluster-containing transcription factor Upc2A in Candida glabrataPreprint
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Genome-wide location profiling of Upc2p, a regulator of sterol biosynthesis and azole resistance in Candida albicans
Znaidi, S., Weber, S., Al-Abdin, O. Z., Bomme, P., Saidane, S., Drouin, S., Lemieux, S., Deken, X. D., Robert, F., & Raymond, M. (2008) · Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles)
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Candida albicans Zinc Cluster Protein Upc2p Confers Resistance to Antifungal Drugs and Is an Activator of Ergosterol Biosynthetic Genes
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Role of Candida albicans Transcription Factor Upc2p in Drug Resistance and Sterol Metabolism
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The UPC2 Promoter in Candida albicans Contains Two cis -Acting Elements That Bind Directly to Upc2p, Resulting in Transcriptional Autoregulation
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A Gain-of-Function Mutation in the Transcription Factor Upc2p Causes Upregulation of Ergosterol Biosynthesis Genes and Increased Fluconazole Resistance in a Clinical Candida albicans Isolate
Dunkel, N., Liu, T. T., Barker, K. S., Homayouni, R., Morschhäuser, J., & Rogers, P. D. (2008) · Eukaryotic Cell · doi:10.1128/ec.00103-08 · Cited by 236 · see citing works

Authors: Znaidi, S., Weber, S., Zin Al-Abdin, O., Bomme, P., Saidane, S., Drouin, S., Lemieux, S., De Deken, X., Robert, F., & Raymond, M.
Affiliations: Institute for Research in Immunology and Cancer (CA)
Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Québec, Canada
Université de Lille (FR)
Université Libre de Bruxelles (BE)
Institut de Recherches Cliniques de Montréal (affiliated with Université de Montréal), Montreal, Québec, Canada
Corresponding author: Raymond, Martine
ORCID: Znaidi, Sadri
Weber, Sandra
Bomme, Perrine
Drouin, Simon
Venue: Eukaryotic Cell
Publisher: American Society for Microbiology
Published: 2008-05
Volume: 7
Issue: 5
Pages: 836-847
ISSN: 1535-9778 (ISSN-L)
1535-9786
DOI: 10.1128/ec.00070-08
PMC: PMC2394978
OpenAlex: W2157149808
Semantic Scholar: 52cb6cbded8e4120b39613b447fe88c3c49585fd
Cited by: 119
References: 62
Citations by year: 2026: 6 · 2025: 3 · 2024: 6 · 2023: 7 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 5 · 2018: 5 · 2017: 7 · 2016: 3 · 2015: 5 · 2014: 11 · 2013: 6 · 2012: 4
FWCI: 5.34
Type: journal article
Language: en
Open access: diamond
doi.org
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Eukaryotic Cell (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
Funders: Canadian Institutes of Health Research (CTP79843, MT-15679)
Natural Sciences and Engineering Research Council of Canada (312023-2005)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords: Candida albicans, transcription factors, zinc cluster transcription factors, sterol metabolism, ergosterol biosynthesis, drug efflux pumps, MDR1, CDR1, promoter binding, transcriptional regulation, lovastatin, hypoxia, sulfur amino acid metabolism, ribosomal subunits
MeSH terms: Azoles, Binding Sites, Candida albicans, Fungal Proteins, Promoter Regions, Genetic, Recombinant Fusion Proteins, Sterols, Transcription Factors, Transcription, Genetic, Gene Expression Regulation, Fungal, Genome, Fungal, Oligonucleotide Array Sequence Analysis, Amino Acid Motifs, Gene Expression Profiling, Drug Resistance, Fungal, Chromatin Immunoprecipitation

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

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