@article{1c6c6e27985d4408b1b7fc4482a11d42,
title = "A Genome-wide Functional Signature Ontology Map and Applications to Natural Product Mechanism of Action Discovery",
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",
author = "McMillan, {Elizabeth A.} and Gino Kwon and Clemenceau, {Jean R.} and Fisher, {Kurt W.} and Vaden, {Rachel M.} and Shaikh, {Anam F.} and Neilsen, {Beth K.} and David Kelly and Potts, {Malia B.} and Sung, {Yeo Jin} and Saurabh Mendiratta and Hight, {Suzie K.} and Yunji Lee and MacMillan, {John B.} and Lewis, {Robert E.} and Kim, {Hyun Seok} and White, {Michael A.}",
note = "Funding Information: This research was supported by an NIH grant U41AT008718 to M.A.W. and J.B.M. from the NIH/NCCIH, grant I-1689 from the Welch Foundation to J.B.M., grant to H.S.K. from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education ( 2014R1A1A2057232 and 2017R1A2B2006777 ). E.A.McM. was supported by NIH training grant 5T32GM8203-27 . R.M.V. was supported by CPRIT training grant RP140110 and NIH training grant 5T32CA124334-09 . Funding Information: This research was supported by an NIH grant U41AT008718 to M.A.W. and J.B.M. from the NIH/NCCIH, grant I-1689 from the Welch Foundation to J.B.M. grant to H.S.K. from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2014R1A1A2057232 and 2017R1A2B2006777). E.A.McM. was supported by NIH training grant 5T32GM8203-27. R.M.V. was supported by CPRIT training grant RP140110 and NIH training grant 5T32CA124334-09. Conceptualization, M.A.W. H.S.K. E.A.McM. J.B.M. and M.B.P.; Methodology, M.A.W. H.S.K. E.A.McM.; Software, E.A.McM. J.R.C. and G.K.; Formal Analysis, E.A.McM. G.K. Y.-J.S.; Investigation, E.A.McM. R.M.V. A.F.S. M.B.P. S.M. S.K.H. K.W.F. B.K.N. D.K. Y.-J.S. and Y.L.; Writing, E.A.McM. H.S.K. M.A.W. M.B.P. J.B.M. and S.K.H.; Supervision, R.E.L. J.B.M. H.S.K. and M.A.W.; Funding, M.A.W. H.S.K. J.B.M. and R.E.L. The authors have no conflicts of interest to report. M.A.W. R.M.V. and E.A.McM. are current employees of Pfizer. Publisher Copyright: {\textcopyright} 2019 Elsevier Ltd",
year = "2019",
month = oct,
day = "17",
doi = "10.1016/j.chembiol.2019.07.008",
language = "English (US)",
volume = "26",
pages = "1380--1392.e6",
journal = "Cell Chemical Biology",
issn = "2451-9448",
publisher = "Elsevier Inc.",
number = "10",
}