High-resolution chemical dissection of a model eukaryote reveals targets, pathways and gene functions.
Dominic Hoepfner, Stephen B Helliwell, Heather Sadlish, Sven Schuierer, Ireos Filipuzzi, Sophie Brachat, Bhupinder Bhullar, Uwe Plikat, Yann Abraham, Marc Altorfer, Thomas Aust, Lukas Baeriswyl, Raffaele Cerino, Lena Chang, David Estoppey, Juerg Eichenberger, Mathias Frederiksen, Nicole Hartmann, Annika Hohendahl, Britta Knapp, Philipp Krastel, Nicolas Melin, Florian Nigsch, Edward J Oakeley, Virginie Petitjean, Frank Petersen, Ralph Riedl, Esther K Schmitt, Frank Staedtler, Christian Studer, John A Tallarico, Stefan Wetzel, Mark C Fishman, Jeffrey A Porter, N Rao Movva
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.
Microbiol. Res. 2014 Feb-Mar; 169:107-20
This study tested 1641 proprietary compounds (named CMBxxx) and 136 reference compounds with known modes of action. We only loaded the data for the 136 known compounds because proprietary compounds were not associated with any chemical structures, accession numbers or compound names (other than an internal ID number), thus preventing their follow-up analysis or validation.
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