D. Kuo, K. Tan, G. Zinman, T. Ravasi, Z. Bar-Joseph, T. Ideker
Genome Biol., 11(7):R77, (2010)
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.
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.
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.