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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 
Journal Title
 Cell Chemical Biology 
ISSN
 2451-9456 
Issue Date
2019
Keywords
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).
Full Text
https://www.sciencedirect.com/science/article/pii/S2451945619302399
DOI
10.1016/j.chembiol.2019.07.008
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Kim, Hyun Seok(김현석) ORCID logo https://orcid.org/0000-0003-4498-8690
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/173137
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