A Novel Sterol-Signaling Pathway Governs Azole Antifungal Drug Resistance and Hypoxic Gene Repression in Saccharomyces cerevisiae
Open accessAbstract
Abstract During antifungal drug treatment and hypoxia, genetic and epigenetic changes occur to maintain sterol homeostasis and cellular function. In this study, we show that SET domain-containing epigenetic factors govern drug efficacy to the medically relevant azole class of antifungal drugs. Upon this discovery, we determined that Set4 is induced when Saccharomyces cerevisiae are treated with azole drugs or grown under hypoxic conditions; two conditions that deplete cellular ergosterol and increase sterol precursors. Interestingly, Set4 induction is controlled by the sterol-sensing transcription factors, Upc2 and Ecm22. To determine the role of Set4 on gene expression under hypoxic conditions, we performed RNA-sequencing analysis and showed that Set4 is required for global changes in gene expression. Specifically, loss of Set4 led to an upregulation of nearly all ergosterol genes, including ERG11 and ERG3, suggesting that Set4 functions in gene repression. Furthermore, mass spectrometry analysis revealed that Set4 interacts with the hypoxic-specific transcriptional repressor, Hap1, where this interaction is necessary for Set4 recruitment to ergosterol gene promoters under hypoxia. Finally, an erg3Δ strain, which produces precursor sterols but lacks ergosterol, expresses Set4 under untreated aerobic conditions. Together, our data suggest that sterol precursors are needed for Set4 induction through an Upc2-mediated mechanism. Overall, this new sterol-signaling pathway governs azole antifungal drug resistance and mediates repression of sterol genes under hypoxic conditions.
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Conflicting results have been observed for the effect of Hap1 on the expression of ERG genes during anaerobic conditions.
“However, conflicting results have been observed for the effect of Hap1 on the expression of ERG genes during anaerobic conditions [75,96,99,100].”
From Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae (2020) · cites this paper as [99]
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References 68 · Cited by 33
Research works printed but not linked: 5
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- Authors
- Serratore, N. D., Baker, K. M., Macadlo, L. A., Gress, A. R., Powers, B. L., Atallah, N., Westerhouse, K. M., Hall, M. C., Weake, V. M., & Briggs, S. D.
- Affiliations
- Purdue University West Lafayette (US)
- Purdue University Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907
- Corresponding author
- Briggs, Scott D
- Venue
- Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-03-01
- Volume
- 208
- Issue
- 3
- Pages
- 1037-1055
- ISSN
- 0016-6731 (ISSN-L)
- 1943-2631
- PMC
- PMC5844321
- OpenAlex
- W2776156805
- Cited by
- 33
- References
- 68
- Citations by year
- 2024: 5 · 2023: 5 · 2022: 8 · 2021: 7 · 2020: 2 · 2019: 3 · 2018: 3
- FWCI
- 0.89
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Eye Institute (R01EY024905)
- National Cancer Institute (P30CA023168, P30CA082709)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
- Keywords
- epigenetic regulation, hypoxia, sterol homeostasis, ergosterol, sterol precursors, UPC2, HAP1, transcriptional repression, ERG11, ERG3, Saccharomyces cerevisiae
- MeSH terms
- Hypoxia, Antifungal Agents, Azoles, Promoter Regions, Genetic, Saccharomyces cerevisiae, Sterols, Signal Transduction, Gene Expression Profiling, Drug Resistance, Fungal, Saccharomyces cerevisiae Proteins, Epigenesis, Genetic
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