Paper

Utilizing gene co-expression networks with the rat kidney TXG-MAPr tool to enhance safety assessment, biomarker identification and human translation

Hugo Van Kessel, Wijaya, Lukas S, Fisher, Ciaran P, Elmore, Susan A, Brown, Colin, Stevens, James L, Teague, Claire R, Heinz-Taheny, Kathleen M, Kunnen, Steven J, Chung, Git, Trairatphisan, Panuwat, Saez-Rodriguez, Julio, Goldstein, Keith M, Callegaro, Giulia, Pye, Keith, Sutherland, Jeffrey J, Van De Water, Bob

2025,2023

Overview

Toxicogenomic data represent a valuable source of biological information at molecular and cellular level to understand unanticipated organ toxicities. Weighted gene co-expression networks analysis can reduce the complexity of gene-level transcriptomic data to a set of biological response-networks useful for providing insights into mechanisms of drug-induced adverse outcomes. In this study, we have built co-regulated gene networks (modules) from the TG-GATEs and DrugMatrix rat kidney datasets consisting of time- and dose-response data for 180 compounds, including nephrotoxicants. Data from the 347 modules were incorporated into the rat kidney TXG-MAPr web tool, a user-friendly interface that enables visualization and analysis of module perturbations, quantified by a module eigengene score (EGS) for each treatment condition. Several modules annotated for cellular stress, renal injury and inflammation were statistically associated with concurrent renal pathologies, including modules that contain both well-known and novel renal biomarker genes. In addition, many rat kidney modules contain well annotated, robust gene networks that are preserved across transcriptome datasets, suggesting that these biological networks translate to other (drug-induced) kidney injury cases. Moreover, preservation analysis of human kidney transcriptomic data provided a quantitative metric to assess the likelihood that rat kidney modules, and the associated biological interpretation, translate from non-clinical species to human. In conclusion, the rat kidney TXG-MAPr enables uploading and analysis of kidney gene expression data in the context of rat kidney co-expression networks, which could identify possible safety liabilities and/or mechanisms that can lead to adversity for chemical or drug candidates.Competing Interest StatementJSR reports funding from GSK, Pfizer and Sanofi and fees/honoraria from Travere Therapeutics, Stadapharm, Astex, Owkin, Pfizer and Grunenthal. PT is a Sanofi employee and may hold shares and/or stock options in the company. All the other authors have declared no competing interests.Footnotes* Abstract and introduction slightly updated; Methods section updated by more clearly describing the module association with pathology, including a resource table and including a link to the R-script to run the WGCNA and module preservation; Discussion section updated by including comparison of co-expression networks with literature and to make some conclusions more clear; Figure 5 revised; Included a new Figure S10; Author affiliations updated; Updated some supplementary figures and tables.* https://txg-mapr.eu/login/

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Biomarkers / Cellular stress response / Drug development / Gene expression / Kidneys / Pharmacology and Toxicology / Transcriptomes / Transcriptomics