Nature Chemical Biology
Nature Chemical Biology
5 years ago

Functional annotation of chemical libraries across diverse biological processes

Functional annotation of chemical libraries across diverse biological processes
Scott W Simpkins, Charles Boone, Katsuhiko Shirahige, Hiroyuki Osada, Raamesh Deshpande, Grant W Brown, Eva DeRango-Adem, Mami Yoshimura, Nikko P Torres, Hamid Safizadeh, Marissa A LeBlanc, Karen Kubo, Minoru Yoshida, Yoko Yashiroda, Anastasia Baryshnikova, Reika Okamoto, Jolanda van Leeuwen, Chad L Myers, Justin Nelson, Kerry Andrusiak, Abraham A Gebre, Jacqueline M Barber, Sheena C Li, Yoshikazu Ohya, Michael Costanzo, Hiroyuki Hirano, Erin Wilson, Jeff S Piotrowski, Brenda Andrews, Hiroki Okada
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.

Publisher URL: http://dx.doi.org/10.1038/nchembio.2436

DOI: 10.1038/nchembio.2436

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.