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Nat Chem Biol. 2017 Sep;13(9):982-993. doi: 10.1038/nchembio.2436. Epub 2017 Jul 24.

Functional annotation of chemical libraries across diverse biological processes.

Author information

1
RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan.
2
Department of Computer Science and Engineering, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.
3
Bioinformatics and Computational Biology Program, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.
4
Department of Electrical and Computer Engineering, University of Minnesota-Twin Cities, Minneapolis, Minnesota, USA.
5
Department of Integrated Biosciences, Graduate School of Frontier Sciences, University of Tokyo, Kashiwa, Chiba, Japan.
6
Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.
7
Institute of Molecular and Cellular Biosciences, Center for Epigenetic Disease, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
8
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey, USA.
9
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.

Abstract

Chemical-genetic approaches offer the potential for unbiased functional annotation of chemical libraries. Mutations can alter the response of cells in the presence of a compound, revealing chemical-genetic interactions that can elucidate a compound's mode of action. We developed a highly parallel, unbiased yeast chemical-genetic screening system involving three key components. First, in a drug-sensitive genetic background, we constructed an optimized diagnostic mutant collection that is predictive for all major yeast biological processes. Second, we implemented a multiplexed (768-plex) barcode-sequencing protocol, enabling the assembly of thousands of chemical-genetic profiles. Finally, based on comparison of the chemical-genetic profiles with a compendium of genome-wide genetic interaction profiles, we predicted compound functionality. Applying this high-throughput approach, we screened seven different compound libraries and annotated their functional diversity. We further validated biological process predictions, prioritized a diverse set of compounds, and identified compounds that appear to have dual modes of action.

PMID:
28759014
PMCID:
PMC6056180
DOI:
10.1038/nchembio.2436
[Indexed for MEDLINE]
Free PMC Article

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