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Integrating yeast chemical genomics and mammalian cell pathway analysis

Authors: Fu-lai Zhou1,2, Sheena C Li3, Yue Zhu1,2, Wan-jing Guo1,2, Li-jun Shao1,2, Justin Nelson4, Scott Simpkins4, De-hua Yang1, Qing Liu1, Yoko Yashiroda3, Jin-biao Xu5, Yao-yue Fan5, Jian-min Yue5, Minoru Yoshida3,6,7, Tian Xia8, Chad L Myers4, Charles Boone3,9, Ming-wei Wang1,2
1 The National Center for Drug Screening and the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai 201203, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 RIKEN Center for Sustainable Resource Science, Wako, Saitama 3510198, Japan
4 Bioinformatics and Computational Biology Program, University of Minnesota-Twin Cities, Minneapolis, Minnesota 55455, USA
5 The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
6 Department of Biology, The University of Tokyo, Bunkyo-ku, Tokyo 1138657, Japan
7 Collaborative Research for Innovative Microbiology, The University of Tokyo, Bunkyo-ku, Tokyo 1138657, Japan
8 Department of Electronics and Information Engineering, Huazhong University of Science and Technology, Wuhan 430074, China
9 Donnelly Centre and Department of Molecular Genetics, University of Toronto, Ontario M5S 3E1, Canada
Correspondence to: Chad L Myers: chadm@umn.edu, Charles Boone: charlie.boone@utoronto.ca, Ming-wei Wang: mwwang@simm.ac.cn,
DOI: 10.1038/s41401-019-0231-y
Received: 8 January 2019
Accepted: 14 March 2019
Advance online: 28 May 2019

Abstract

Chemical genomics has been applied extensively to evaluate small molecules that modulate biological processes in Saccharomyces cerevisiae. Here, we use yeast as a surrogate system for studying compounds that are active against metazoan targets. Large-scale chemical-genetic profiling of thousands of synthetic and natural compounds from the Chinese National Compound Library identified those with high-confidence bioprocess target predictions. To discover compounds that have the potential to function like therapeutic agents with known targets, we also analyzed a reference library of approved drugs. Previously uncharacterized compounds with chemical-genetic profiles resembling existing drugs that modulate autophagy and Wnt/β-catenin signal transduction were further examined in mammalian cells, and new modulators with specific modes of action were validated. This analysis exploits yeast as a general platform for predicting compound bioactivity in mammalian cells.
Keywords: yeast; chemical genomics; tubulin cytoskeleton assembly; autophagy; Wnt/β-catenin signaling pathway

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