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

Elizabeth A. McMillan, Gino Kwon, Jean R. Clemenceau, Kurt W. Fisher, Rachel M. Vaden, Anam F. Shaikh, Beth K. Neilsen, David Kelly, Malia B. Potts, Yeo Jin Sung, Saurabh Mendiratta, Suzie K. Hight, Yunji Lee, John B. MacMillan, Robert E. Lewis, Hyun Seok Kim, Michael A. White

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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).

Original languageEnglish (US)
Pages (from-to)1380-1392.e6
JournalCell Chemical Biology
Volume26
Issue number10
DOIs
StatePublished - Oct 17 2019

Keywords

  • cell regulatory networks
  • chemical genetics
  • functional genomics
  • mechanism of action
  • natural products
  • network pharmacology

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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