Heme Levels Switch the Function of Hap1 of Saccharomyces cerevisiae between Transcriptional Activator and Transcriptional Repressor
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Changes in oxygen levels cause widespread changes in gene expression in organisms ranging from bacteria to humans. In Saccharomyces cerevisiae, this response is mediated in part by Hap1, originally identified as a heme-dependent transcriptional activator that functions during aerobic growth. We show here that Hap1 also plays a significant and direct role under hypoxic conditions, not as an activator, but as a repressor. The repressive activity of Hap1 controls several genes, including three ERG genes required for ergosterol biosynthesis. Chromatin immunoprecipitation experiments showed that Hap1 binds to the ERG gene promoters, while additional experiments showed that the corepressor Tup1/Ssn6 is recruited by Hap1 and is also required for repression. Furthermore, mutational analysis demonstrated that conserved Hap1 binding sites in the ERG5 5' regulatory region are required for repression. The switch of Hap1 from acting as a hypoxic repressor to an aerobic activator is determined by heme, which is synthesized only in the presence of oxygen. The ability of Hap1 to function as a ligand-dependent repressor and activator is a property shared with mammalian nuclear hormone receptors and likely allows greater transcriptional control by Hap1 in response to changing oxygen levels.
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Hap1 seems to shift from an activator to a transcriptional repressor when oxygen availability decreases.
“Importantly, Hap1 seems to shift from an activator to a transcriptional repressor when oxygen availability decreases [98].”
From Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae (2020) · cites this paper as [98]
Several genome-wide expression studies under low oxygen conditions have reflected that the pattern of expression differs among ERG genes, although some general trends can be extracted.
“Several genome-wide expression studies based on microarray and RNA-Seq analyses under low oxygen conditions have reflected that the pattern of expression differs among ERG genes, although some general trends can be extracted [94,96,98,100,101,102,103].”
From Regulation of Ergosterol Biosynthesis in Saccharomyces cerevisiae (2020) · cites this paper as [98]
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- Authors
- Hickman, M. J., & Winston, F.
- Affiliations
- Harvard University (US)
- Corresponding author
- Winston, Fred
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2007-11
- Volume
- 27
- Issue
- 21
- Pages
- 7414-7424
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC2169065
- OpenAlex
- W2126362614
- Cited by
- 137
- References
- 69
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 8 · 2023: 4 · 2022: 6 · 2021: 3 · 2020: 10 · 2019: 3 · 2018: 9 · 2017: 9 · 2016: 4 · 2015: 4 · 2014: 11 · 2013: 8 · 2012: 6
- FWCI
- 4.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (F32GM071102, R01GM045720, F32GM71102, GM 45720)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Keywords
- HAP1, heme, transcriptional repression, transcriptional activation, hypoxia, oxygen sensing, ERG gene, ergosterol biosynthesis, nuclear receptors, Saccharomyces cerevisiae
- MeSH terms
- Aerobiosis, Anaerobiosis, Base Sequence, Binding Sites, Cytochrome P-450 Enzyme System, DNA-Binding Proteins, Genes, Fungal, Heme, Molecular Sequence Data, Nuclear Proteins, Oxidoreductases, Promoter Regions, Genetic, Protein Binding, Repressor Proteins, Saccharomyces cerevisiae, Transcription Factors, Transcription, Genetic, Trans-Activators, Gene Expression Regulation, Fungal, HSP70 Heat-Shock Proteins, HSP90 Heat-Shock Proteins, Oligonucleotide Array Sequence Analysis, Saccharomyces cerevisiae Proteins, Cytochromes c
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