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High-resolution chemical dissection of a model eukaryote reveals targets, pathways and gene functions
Open accessAbstract
Due to evolutionary conservation of biology, experimental knowledge captured from genetic studies in eukaryotic model organisms provides insight into human cellular pathways and ultimately physiology. Yeast chemogenomic profiling is a powerful approach for annotating cellular responses to small molecules. Using an optimized platform, we provide the relative sensitivities of the heterozygous and homozygous deletion collections for nearly 1800 biologically active compounds. The data quality enables unique insights into pathways that are sensitive and resistant to a given perturbation, as demonstrated with both known and novel compounds. We present examples of novel compounds that inhibit the therapeutically relevant fatty acid synthase and desaturase (Fas1p and Ole1p), and demonstrate how the individual profiles facilitate hypothesis-driven experiments to delineate compound mechanism of action. Importantly, the scale and diversity of tested compounds yields a dataset where the number of modulated pathways approaches saturation. This resource can be used to map novel biological connections, and also identify functions for unannotated genes. We validated hypotheses generated by global two-way hierarchical clustering of profiles for (i) novel compounds with a similar mechanism of action acting upon microtubules or vacuolar ATPases, and (ii) an un-annotated ORF, YIL060w, that plays a role in respiration in the mitochondria. Finally, we identify and characterize background mutations in the widely used yeast deletion collection which should improve the interpretation of past and future screens throughout the community. This comprehensive resource of cellular responses enables the expansion of our understanding of eukaryotic pathway biology.
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“suggesting that the topology of genetic networks connecting genes within protein complexes by uniform sets of genetic interactions is conserved in higher eukaryotes”
From A global genetic interaction network maps a wiring diagram of cellular function (2016) · cites this paper as [30]
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Self-citation
Metadata
- Authors
- Hoepfner, D., Helliwell, S. B., Sadlish, H., Schuierer, S., Filipuzzi, I., Brachat, S., Bhullar, B., Plikat, U., Abraham, Y., Altorfer, M., Aust, T., Baeriswyl, L., Cerino, R., Chang, L., Estoppey, D., Eichenberger, J., Frederiksen, M., Hartmann, N., Hohendahl, A., Knapp, B., Krastel, P., Melin, N., Nigsch, F., Oakeley, E. J., Petitjean, V., Petersen, F., Riedl, R., Schmitt, E. K., Staedtler, F., Studer, C., Tallarico, J. A., Wetzel, S., Fishman, M. C., Porter, J. A., & Movva, N. R.
- Affiliations
- Novartis (Switzerland) (CH)
- Corresponding author
- Hoepfner, Dominic
- ORCID
- Venue
- Microbiological Research
- Publisher
- Elsevier BV
- Published
- 2014-02
- Volume
- 169
- Issue
- 2-3
- Pages
- 107-120
- ISSN
- 0944-5013 (ISSN-L)
- OpenAlex
- W2013242034
- Cited by
- 166
- References
- 50
- Citations by year
- 2026: 5 · 2025: 11 · 2024: 12 · 2023: 6 · 2022: 13 · 2021: 6 · 2020: 11 · 2019: 23 · 2018: 20 · 2017: 23 · 2016: 12 · 2015: 18 · 2014: 5
- FWCI
- 5.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Microbiological Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Novartis Institutes for BioMedical Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Keywords
- chemogenomics, fatty acid synthase inhibition, microtubule inhibitors, mitochondrial respiration, background mutations, Saccharomyces cerevisiae
- MeSH terms
- Antifungal Agents, Molecular Sequence Data, Phylogeny, Saccharomyces cerevisiae, Gene Expression Regulation, Fungal, Drug Resistance, Fungal, Saccharomyces cerevisiae Proteins, Biosynthetic Pathways, High-Throughput Screening Assays
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