RT Journal Article
SR Electronic
T1 Functional Annotation of Chemical Libraries across Diverse Biological Processes
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 112557
DO 10.1101/112557
A1 Jeff S. Piotrowski
A1 Sheena C. Li
A1 Raamesh Deshpande
A1 Scott W. Simpkins
A1 Justin Nelson
A1 Yoko Yashiroda
A1 Jacqueline M. Barber
A1 Hamid Safizadeh
A1 Erin Wilson
A1 Hiroki Okada
A1 Abraham A. Gebre
A1 Karen Kubo
A1 Nikko P. Torres
A1 Marissa A. LeBlanc
A1 Kerry Andrusiak
A1 Reika Okamoto
A1 Mami Yoshimura
A1 Eva DeRango-Adem
A1 Jolanda van Leeuwen
A1 Katsuhiko Shirahige
A1 Anastasia Baryshnikova
A1 Grant W. Brown
A1 Hiroyuki Hirano
A1 Michael Costanzo
A1 Brenda Andrews
A1 Yoshikazu Ohya
A1 Hiroyuki Osada
A1 Minoru Yoshida
A1 Chad L. Myers
A1 Charles Boone
YR 2017
UL http://biorxiv.org/content/early/2017/02/28/112557.abstract
AB 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.