Cell Chemical Biology
Volume 26, Issue 10, 17 October 2019, Pages 1380-1392.e6
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Article
A Genome-wide Functional Signature Ontology Map and Applications to Natural Product Mechanism of Action Discovery

https://doi.org/10.1016/j.chembiol.2019.07.008Get rights and content
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Highlights

  • Generation of genome-wide gene/gene and gene/chemical similarity maps

  • Annotation of novel gene function and cooperatively among biological pathways

  • Parallel mechanism of action predictions for thousands of NPFs with diverse cell biological effects

Summary

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

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

Cited by (0)

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Present address: Oncology Research and Development, Pfizer Inc., San Diego, CA 92121, USA

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These authors contributed equally

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