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

Hoepfner, D and Helliwell, SB and Sadlish, H and Schuierer, S and Filipuzzi, I and Brachat, S and Bhullar, B and Plikat, U and Abraham, Y and Altorfer, M and Aust, T and Baeriswyl, L and Cerino, R and Chang, L and Estoppey, D and Eichenberger, J and Frederiksen, M and Hartmann, N and Hohendahl, A and Knapp, B and Krastel, P and Melin, N and Nigsch, F and Oakeley, EJ and Petitjean, V and Petersen, F and Riedl, R and Schmitt, EK and Staedtler, F and Studer, C and Tallarico, JA and Wetzel, S and Fishman, MC and Porter, JA and Movva, NR (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 (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. (C) 2013 Elsevier GmbH. All rights reserved

Item Type: Article
Additional Information: NIBR author: Hoepfner, D institute: NIBR contributor address: Novartis Inst BioMed Res, CH-4056 Basel, Switzerland dominic.hoepfner@novartis.com; Novartis Inst BioMed Res, Cambridge, MA 02139 USA ; Novartis Inst BioMed Res, CH-4056 Basel, Switzerland; Hoepfner, D; Novartis Inst BioMed Res, Novartis Campus, CH-4056 Basel, Switzerland
Date Deposited: 13 Oct 2015 13:12
Last Modified: 04 Jul 2016 23:45
URI: https://oak.novartis.com/id/eprint/22613

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