Functional Annotation of Chemical Libraries across Diverse Biological Processes

Piotrowski, J. S.; Li, S. C.; Deshpande, R.; Simpkins, S. W.; Nelson, J.; Yashiroda, Y.; Barber, J.; Safizadeh, H.; Wilson, E.; Okada, H.; Gebre, A.; Kubo, K.; Torres, N.; LeBlanc, M.; Andrusiak, K.; Okamoto, R.; Yoshimura, M.; DeRango-Adem, E.; van Leeuwen, J.; Shirahige, K.; Baryshnikova, A.; Brown, G. W.; Hirano, H.; Costanzo, M.; Andrews, B.; Ohya, Y.; Osada, H.; Yoshida, M.; Myers, C. L.; Boone, C.

doi:10.1101/112557

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bioRxiv · 10.1101/112557

Functional Annotation of Chemical Libraries across Diverse Biological Processes

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Abstract

Chemical-genetic approaches offer the potential for unbiased functional annotation of chemical libraries. Mutations can alter the response of cells to a compound, revealing chemical-genetic interactions that can elucidate a compounds mode of action. We developed a highly parallel and 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 all major yeast biological processes. Second, we implemented a multiplexed (768-plex) barcode sequencing protocol, enabling 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 7 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.

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Piotrowski, J. S., Li, S. C., Deshpande, R., Simpkins, S. W., Nelson, J., Yashiroda, Y., Barber, J., Safizadeh, H., Wilson, E., Okada, H., Gebre, A., Kubo, K., Torres, N., LeBlanc, M., Andrusiak, K., Okamoto, R., Yoshimura, M., DeRango-Adem, E., van Leeuwen, J., Shirahige, K., Baryshnikova, A., Brown, G. W., Hirano, H., Costanzo, M., Andrews, B., Ohya, Y., Osada, H., Yoshida, M., Myers, C. L., Boone, C.. 2017-02-28. Functional Annotation of Chemical Libraries across Diverse Biological Processes. https://doi.org/10.1101/112557

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