A Genome-wide Functional Signature Ontology Map and Applications to Natural Product Mechanism of Action Discovery
Authors
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
Citation
Cell Chemical Biology, Vol.26(10) : 1380-1392.e6, 2019
cell regulatory networks ; chemical genetics ; functional genomics ; mechanism of action ; natural products ; network pharmacology
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).