title: Elucidating the modes of action for bioactive compounds in a cell-specific manner by large-scale chemically-induced transcriptomics.
abstract: The identification of the modes of action of bioactive compounds is a major challenge in chemical systems biology of diseases. Genome-wide expression profiling of transcriptional responses to compound treatment for human cell lines is a promising unbiased approach for the mode-of-action analysis. Here we developed a novel approach to elucidate the modes of action of bioactive compounds in a cell-specific manner using large-scale chemically-induced transcriptome data acquired from the Library of Integrated Network-based Cellular Signatures (LINCS), and analyzed 16,268 compounds and 68 human cell lines. First, we performed pathway enrichment analyses of regulated genes to reveal active pathways among 163 biological pathways. Next, we explored potential target proteins (including primary targets and off-targets) with cell-specific transcriptional similarity using chemical-protein interactome. Finally, we predicted new therapeutic indications for 461 diseases based on the target proteins. We showed the usefulness of the proposed approach in terms of prediction coverage, interpretation, and large-scale applicability, and validated the new prediction results experimentally by an in vitro cellular assay. The approach has a high potential for advancing drug discovery and repositioning.
authors.affiliation: Division of System Cohort, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Iwata
authors.affiliation: Division of System Cohort, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
authors.forename: Ryusuke
authors.initials: R
authors.lastname: Sawada
authors.affiliation: Division of System Cohort, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Iwata
authors.affiliation: School of Life Science and Technology, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo, 152-8550, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kotera
authors.affiliation: Division of System Cohort, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.|Institute for Advanced Study, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Fukuoka 812-8582, Japan.|PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamanishi
mesh_terms: D001688:Biological Products / Q000494:pharmacology*; D002460:Cell Line; D019295:Computational Biology / Q000379:methods*; D020869:Gene Expression Profiling; D006801:Humans; D053858:Metabolic Networks and Pathways / Q000235:genetics; D011485:Protein Binding; D049490:Systems Biology / Q000379:methods
chemical_list: D001688:Biological Products