The Department of Chemical and Systems Biology Presents

Michael Tyers, PhD
Professor Institute for Research in Immunology and Cancer
University of Montreal

“A chemical snapshot of the human genetic interaction landscape”

Genetic mutations that alter the response to drugs and other bioactive compounds can inform chemical mechanism-of-action and reveal the underlying genetic network structure of the cell. We have used genome-wide CRISPR/Cas9 knockout screens in human cells to generate isogenic chemical-gene interaction profiles for hundreds of mechanistically diverse bioactive small molecules, including many approved drugs. The resultant large-scale network of >10,000 high confidence chemical-gene interactions identified specific genetic resistance and sensitization signatures and uncovered novel mechanisms-of-action for many known drugs and uncharacterized compounds. Dense modules in the network revealed the genetic organization of mitotic regulation, the DNA damage response, phosphorylation-based signaling, metabolism, epigenetic control, and responses to environmental stresses. This chemomgenomics dataset has yielded insights into multi-drug sensitization and resistance mechanisms, new gene functions, the basis for chemical synergism, and the genetic landscape of human cells.

Reading Material:

1. Bertomeu, Tyers, et al., A High-Resolution Genome-Wide CRISPR/Cas9 Viability Screen Reveals Structural Features and Contextual Diversity of the Human Cell-Essential Proteome: Mol Cell Biol 38:e00302-17. https://doi.org/10.1128/MCB.00302-17
2. Hill, Tyers et al., Robust cullin-RING ligase function is established by a multiplicity of poly-ubiquitylation pathways: eLife 2019;8:e51163. DOI: https://doi.org/10.7554/eLife.51163

(Faculty host: James E. Ferrell)