A Genome-wide Functional Signature Ontology Map and Applications to Natural Product Mechanism of Action Discovery.,Cell Chemical Biology

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A Genome-wide Functional Signature Ontology Map and Applications to Natural Product Mechanism of Action Discovery.
Cell Chemical Biology ( IF 6.6 ) Pub Date : 2019-08-01 , DOI: 10.1016/j.chembiol.2019.07.008
Elizabeth A McMillan ₁ , Gino Kwon ₂ , Jean R Clemenceau ₁ , Kurt W Fisher ₃ , Rachel M Vaden ₁ , Anam F Shaikh ₄ , Beth K Neilsen ₅ , David Kelly ₅ , Malia B Potts ₁ , Yeo-Jin Sung ₆ , Saurabh Mendiratta ₁ , Suzie K Hight ₁ , Yunji Lee ₆ , John B MacMillan ₇ , Robert E Lewis ₅ , Hyun Seok Kim ₈ , Michael A White ₁

Affiliation

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).

中文翻译：

全基因组功能特征本体图及其在天然产物作用机制发现中的应用。

基于基因表达特征的遗传扰动、化学扰动和疾病状态内部和之间的功能连接性推断可以导致对基因功能、化学作用模式和疾病治疗策略的可行假设的发展。在这里，我们报告了基于 FuSiOn 的亚效细胞表型的全基因组整合，该整合能够对基因网络拓扑进行功能注释、为未知功能的基因分配机制假设以及检测细胞调节系统之间的协作性。将遗传扰动数据与化学扰动表型相结合，可以同时生成数千个未表征的天然产物组分 (NPF) 的作用机制假设。预测的作用机制涵盖广泛的细胞机制，其中许多目前不被认为是“可成药的”。为了能够使用 FuSiOn 作为假设生成资源，所有关联和分析都可以在基于 Web 的开源 GUI (http://fusion.yuhs.ac) 中使用。

更新日期：2019-11-09

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