Identifying multiscale translational safety biomarkers using a network-based systems approach
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- dc.contributor.author Callegaro, Giulia
- dc.contributor.author Schimming, Johannes P.
- dc.contributor.author Piñero González, Janet, 1977-
- dc.contributor.author Kunnen, Steven J.
- dc.contributor.author Wijaya, Lukas
- dc.contributor.author Trairatphisan, Panuwat
- dc.contributor.author van den Berk, Linda
- dc.contributor.author Beetsma, Kim
- dc.contributor.author Furlong, Laura I.
- dc.contributor.author Sutherland, Jeffrey J.
- dc.contributor.author Mollon, Jennifer
- dc.contributor.author Stevens, James L.
- dc.contributor.author van de Water, Bob
- dc.date.accessioned 2023-06-01T12:17:48Z
- dc.date.available 2023-06-01T12:17:48Z
- dc.date.issued 2023
- dc.description.abstract Animal testing is the current standard for drug and chemicals safety assessment, but hazards translation to human is uncertain. Human in vitro models can address the species translation but might not replicate in vivo complexity. Herein, we propose a network-based method addressing these translational multiscale problems that derives in vivo liver injury biomarkers applicable to in vitro human early safety screening. We applied weighted correlation network analysis (WGCNA) to a large rat liver transcriptomic dataset to obtain co-regulated gene clusters (modules). We identified modules statistically associated with liver pathologies, including a module enriched for ATF4-regulated genes as associated with the occurrence of hepatocellular single-cell necrosis, and as preserved in human liver in vitro models. Within the module, we identified TRIB3 and MTHFD2 as a novel candidate stress biomarkers, and developed and used BAC-eGFPHepG2 reporters in a compound screening, identifying compounds showing ATF4-dependent stress response and potential early safety signals.
- dc.description.sponsorship This work was supported by the EU-EFPIA Innovative Medicines Initiative 2 (IMI2) Joint Undertaking TransQST project (grant number 116030) and eTRANSAFE project (grant number 777365) (this Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA), the EC Horizon2020 EU-ToxRisk project (grant number 681002), the European Research & Innovation project funded under the European Commission’s Horizon 2020 program RISK-HUNT3R project (grant number 964537) and the Cosmetics Europe/CEFIC Liver Ontology project.
- dc.format.mimetype application/pdf
- dc.identifier.citation Callegaro G, Schimming JP, Piñero J, Kunnen SJ, Wijaya L, Trairatphisan P, et al. Identifying multiscale translational safety biomarkers using a network-based systems approach. iScience. 2023 Mar 17;26(3):106094. DOI: 10.1016/j.isci.2023.106094
- dc.identifier.doi http://dx.doi.org/10.1016/j.isci.2023.106094
- dc.identifier.issn 2589-0042
- dc.identifier.uri http://hdl.handle.net/10230/57018
- dc.language.iso eng
- dc.publisher Elsevier
- dc.relation.ispartof iScience. 2023 Mar 17;26(3):106094
- dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/116030
- dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/777365
- dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/681002
- dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/964537
- dc.rights © This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
- dc.subject.keyword Gene network
- dc.subject.keyword Bioinformatics
- dc.subject.keyword Transcriptomics
- dc.title Identifying multiscale translational safety biomarkers using a network-based systems approach
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion