Functional annotation of chemical libraries across diverse biological processes

Jeff S. Piotrowski, Sheena C. Li, Raamesh Deshpande, Scott W. Simpkins, Justin Nelson, Yoko Yashiroda, Jacqueline M. Barber, Hamid Safizadeh, Erin Wilson, Hiroki Okada, Abraham A. Gebre, Karen Kubo, Nikko P. Torres, Marissa A. Leblanc, Kerry Andrusiak, Reika Okamoto, Mami Yoshimura, Eva Derango-Adem, Jolanda Van Leeuwen, Katsuhiko ShirahigeAnastasia Baryshnikova, Grant W. Brown, Hiroyuki Hirano, Michael Costanzo, Brenda Andrews, Yoshikazu Ohya, Hiroyuki Osada, Minoru Yoshida, Chad L. Myers, Charles Boone

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)982-993
Number of pages12
JournalNature Chemical Biology
Volume13
Issue number9
DOIs
StatePublished - Sep 1 2017

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