Evolutionary divergence in the fungal response to fluconazole revealed by soft clustering

Handle URI:
http://hdl.handle.net/10754/334580
Title:
Evolutionary divergence in the fungal response to fluconazole revealed by soft clustering
Authors:
Kuo, Dwight; Tan, Kai; Zinman, Guy; Ravasi, Timothy ( 0000-0002-9950-465X ) ; Bar-Joseph, Ziv; Ideker, Trey
Abstract:
Background: Fungal infections are an emerging health risk, especially those involving yeast that are resistant to antifungal agents. To understand the range of mechanisms by which yeasts can respond to anti-fungals, we compared gene expression patterns across three evolutionarily distant species - Saccharomyces cerevisiae, Candida glabrata and Kluyveromyces lactis - over time following fluconazole exposure. Results: Conserved and diverged expression patterns were identified using a novel soft clustering algorithm that concurrently clusters data from all species while incorporating sequence orthology. The analysis suggests complementary strategies for coping with ergosterol depletion by azoles - Saccharomyces imports exogenous ergosterol, Candida exports fluconazole, while Kluyveromyces does neither, leading to extreme sensitivity. In support of this hypothesis we find that only Saccharomyces becomes more azole resistant in ergosterol-supplemented media; that this depends on sterol importers Aus1 and Pdr11; and that transgenic expression of sterol importers in Kluyveromyces alleviates its drug sensitivity. Conclusions: We have compared the dynamic transcriptional responses of three diverse yeast species to fluconazole treatment using a novel clustering algorithm. This approach revealed significant divergence among regulatory programs associated with fluconazole sensitivity. In future, such approaches might be used to survey a wider range of species, drug concentrations and stimuli to reveal conserved and divergent molecular response pathways.
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division; Computational Bioscience Research Center (CBRC); Red Sea Research Center (RSRC)
Citation:
Kuo D, Tan K, Zinman G, Ravasi T, Bar-Joseph Z, et al. (2010) Evolutionary divergence in the fungal response to fluconazole revealed by soft clustering. Genome Biology 11: R77. doi:10.1186/gb-2010-11-7-r77.
Publisher:
BioMed Central
Journal:
Genome Biology
Issue Date:
23-Jul-2010
DOI:
10.1186/gb-2010-11-7-r77
PubMed ID:
20653936
PubMed Central ID:
PMC2926788
Type:
Article
ISSN:
1465-6906
Appears in Collections:
Articles; Red Sea Research Center (RSRC); Computational Bioscience Research Center (CBRC); Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorKuo, Dwighten
dc.contributor.authorTan, Kaien
dc.contributor.authorZinman, Guyen
dc.contributor.authorRavasi, Timothyen
dc.contributor.authorBar-Joseph, Ziven
dc.contributor.authorIdeker, Treyen
dc.date.accessioned2014-11-11T14:30:37Z-
dc.date.available2014-11-11T14:30:37Z-
dc.date.issued2010-07-23en
dc.identifier.citationKuo D, Tan K, Zinman G, Ravasi T, Bar-Joseph Z, et al. (2010) Evolutionary divergence in the fungal response to fluconazole revealed by soft clustering. Genome Biology 11: R77. doi:10.1186/gb-2010-11-7-r77.en
dc.identifier.issn1465-6906en
dc.identifier.pmid20653936en
dc.identifier.doi10.1186/gb-2010-11-7-r77en
dc.identifier.urihttp://hdl.handle.net/10754/334580en
dc.description.abstractBackground: Fungal infections are an emerging health risk, especially those involving yeast that are resistant to antifungal agents. To understand the range of mechanisms by which yeasts can respond to anti-fungals, we compared gene expression patterns across three evolutionarily distant species - Saccharomyces cerevisiae, Candida glabrata and Kluyveromyces lactis - over time following fluconazole exposure. Results: Conserved and diverged expression patterns were identified using a novel soft clustering algorithm that concurrently clusters data from all species while incorporating sequence orthology. The analysis suggests complementary strategies for coping with ergosterol depletion by azoles - Saccharomyces imports exogenous ergosterol, Candida exports fluconazole, while Kluyveromyces does neither, leading to extreme sensitivity. In support of this hypothesis we find that only Saccharomyces becomes more azole resistant in ergosterol-supplemented media; that this depends on sterol importers Aus1 and Pdr11; and that transgenic expression of sterol importers in Kluyveromyces alleviates its drug sensitivity. Conclusions: We have compared the dynamic transcriptional responses of three diverse yeast species to fluconazole treatment using a novel clustering algorithm. This approach revealed significant divergence among regulatory programs associated with fluconazole sensitivity. In future, such approaches might be used to survey a wider range of species, drug concentrations and stimuli to reveal conserved and divergent molecular response pathways.en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.rights.urihttp://creativecommons.org/licenses/by/2.0/en
dc.titleEvolutionary divergence in the fungal response to fluconazole revealed by soft clusteringen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.contributor.departmentComputational Bioscience Research Center (CBRC)en
dc.contributor.departmentRed Sea Research Center (RSRC)en
dc.identifier.journalGenome Biologyen
dc.identifier.pmcidPMC2926788en
dc.eprint.versionPublisher's Version/PDFen
dc.contributor.institutionDepartments of Bioengineering and Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USAen
dc.contributor.institutionDepartments of Internal Medicine and Biomedical Engineering, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USAen
dc.contributor.institutionDepartment of Computer Science, Carnegie Mellon University, 500 Forbes Avenue, Pittsburgh, PA 15213, USAen
dc.contributor.affiliationKing Abdullah University of Science and Technology (KAUST)en
kaust.authorRavasi, Timothyen

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