Functional Annotation of Chemical Libraries across Diverse Biological Processes
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 compound’s 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.
Subject Area
- Biochemistry (11776)
- Bioengineering (8765)
- Bioinformatics (29246)
- Biophysics (14998)
- Cancer Biology (12136)
- Cell Biology (17432)
- Clinical Trials (138)
- Developmental Biology (9433)
- Ecology (14199)
- Epidemiology (2067)
- Evolutionary Biology (18328)
- Genetics (12259)
- Genomics (16813)
- Immunology (11883)
- Microbiology (28124)
- Molecular Biology (11616)
- Neuroscience (61056)
- Paleontology (452)
- Pathology (1875)
- Pharmacology and Toxicology (3239)
- Physiology (4969)
- Plant Biology (10436)
- Synthetic Biology (2889)
- Systems Biology (7348)
- Zoology (1653)