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High-resolution chemical dissection of a model eukaryote reveals targets, pathways and gene functions

Hoepfner, Dominic and Helliwell, Stephen and Sadlish, Heather and Schuierer, Sven and Filipuzzi, Ireos and Brachat, Sophie and Bhullar, Bhupinder and Plikat, Uwe and Abraham, Yann and Altorfer, Marc and Aust, Thomas and Baeriswyl, Lukas and Cerino, Raffaele and Chang, Lena and Estoppey, David and Eichenberger, Juerg and Frederiksen, Mathias and Hartmann, Nicole and Hohendahl, Annika and Knapp, Britta and Krastel, Philipp and Melin, Nicolas and Nigsch, Florian and Oakeley, Edward James and Petitjean, Virginie and Petersen, Frank and Riedl, Ralph and Schmitt, Esther and Staedtler, Frank and Studer, Christian and Tallarico, John and Wetzel, Stefan and Fishman, Mark and Porter, Jeffrey and Movva, Rao (2014) High-resolution chemical dissection of a model eukaryote reveals targets, pathways and gene functions. Microbiological Research, 169 (2-3). pp. 107-120. ISSN 09445013

Abstract

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 (Ole1p and Fas1p), 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 2-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.

Item Type: Article
Additional Information: To streamline the approval process not all authors are included in the legal clearance. All authors will have the possibility to provide input for the final manuscript once the data is cleared for publication.
Keywords: Chemogenomic profiling, target identification, mechanism of action, bioactive molecules, yeast, HIP, HOP
Date Deposited: 13 Oct 2015 13:15
Last Modified: 04 Jul 2016 23:46
URI: https://oak.novartis.com/id/eprint/5424

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