A Genome-wide Functional Signature Ontology Map and Applications to Natural Product Mechanism of Action Discovery

Cell Chem Biol. 2019 Oct 17;26(10):1380-1392.e6. doi: 10.1016/j.chembiol.2019.07.008. Epub 2019 Aug 1.

Abstract

Gene expression signature-based inference of functional connectivity within and between genetic perturbations, chemical perturbations, and disease status can lead to the development of actionable hypotheses for gene function, chemical modes of action, and disease treatment strategies. Here, we report a FuSiOn-based genome-wide integration of hypomorphic cellular phenotypes that enables functional annotation of gene network topology, assignment of mechanistic hypotheses to genes of unknown function, and detection of cooperativity among cell regulatory systems. Dovetailing genetic perturbation data with chemical perturbation phenotypes allowed simultaneous generation of mechanism of action hypotheses for thousands of uncharacterized natural products fractions (NPFs). The predicted mechanism of actions span a broad spectrum of cellular mechanisms, many of which are not currently recognized as "druggable." To enable use of FuSiOn as a hypothesis generation resource, all associations and analyses are available within an open source web-based GUI (http://fusion.yuhs.ac).

Keywords: cell regulatory networks; chemical genetics; functional genomics; mechanism of action; natural products; network pharmacology.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Biological Products / chemistry
  • Biological Products / pharmacology*
  • Drug Discovery*
  • HCT116 Cells
  • HeLa Cells
  • Humans
  • Neoplasms / drug therapy*
  • Neoplasms / genetics*
  • Phenotype
  • Software*
  • Transcriptome
  • Tumor Cells, Cultured

Substances

  • Biological Products