The human hepatocyte TXG-MAPr: gene co-expression network modules to support mechanism-based risk assessment

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  • dc.contributor.author Callegaro, Giulia
  • dc.contributor.author Kunnen, Steven J.
  • dc.contributor.author Trairatphisan, Panuwat
  • dc.contributor.author Grosdidier, Solène
  • dc.contributor.author Niemeijer, Marije
  • dc.contributor.author den Hollander, Wouter
  • dc.contributor.author Guney, Emre
  • dc.contributor.author Piñero González, Janet, 1977-
  • dc.contributor.author Furlong, Laura I., 1971-
  • dc.contributor.author Webster, Yue W.
  • dc.contributor.author Saez-Rodriguez, Julio
  • 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 2022-05-16T06:59:54Z
  • dc.date.available 2022-05-16T06:59:54Z
  • dc.date.issued 2021
  • dc.description.abstract Mechanism-based risk assessment is urged to advance and fully permeate into current safety assessment practices, possibly at early phases of drug safety testing. Toxicogenomics is a promising source of mechanisms-revealing data, but interpretative analysis tools specific for the testing systems (e.g. hepatocytes) are lacking. In this study, we present the TXG-MAPr webtool (available at https://txg-mapr.eu/WGCNA_PHH/TGGATEs_PHH/ ), an R-Shiny-based implementation of weighted gene co-expression network analysis (WGCNA) obtained from the Primary Human Hepatocytes (PHH) TG-GATEs dataset. The 398 gene co-expression networks (modules) were annotated with functional information (pathway enrichment, transcription factor) to reveal their mechanistic interpretation. Several well-known stress response pathways were captured in the modules, were perturbed by specific stressors and showed preservation in rat systems (rat primary hepatocytes and rat in vivo liver), with the exception of DNA damage and oxidative stress responses. A subset of 87 well-annotated and preserved modules was used to evaluate mechanisms of toxicity of endoplasmic reticulum (ER) stress and oxidative stress inducers, including cyclosporine A, tunicamycin and acetaminophen. In addition, module responses can be calculated from external datasets obtained with different hepatocyte cells and platforms, including targeted RNA-seq data, therefore, imputing biological responses from a limited gene set. As another application, donors' sensitivity towards tunicamycin was investigated with the TXG-MAPr, identifying higher basal level of intrinsic immune response in donors with pre-existing liver pathology. In conclusion, we demonstrated that gene co-expression analysis coupled to an interactive visualization environment, the TXG-MAPr, is a promising approach to achieve mechanistic relevant, cross-species and cross-platform evaluation of toxicogenomic data.
  • 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), and the Cosmetics Europe/CEFIC Liver Ontology project.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Callegaro G, Kunnen SJ, Trairatphisan P, Grosdidier S, Niemeijer M, den Hollander W, et al. The human hepatocyte TXG-MAPr: gene co-expression network modules to support mechanism-based risk assessment. Arch Toxicol. 2021 Dec; 95(12): 3745-75. DOI: 10.1007/s00204-021-03141-w
  • dc.identifier.doi http://dx.doi.org/10.1007/s00204-021-03141-w
  • dc.identifier.issn 0340-5761
  • dc.identifier.uri http://hdl.handle.net/10230/53087
  • dc.language.iso eng
  • dc.publisher SpringerOpen
  • dc.relation.projectID info:eu-repo/grantAgreement/H2020/681002
  • dc.relation.projectID info:eu-repo/grantAgreement/H2020/116030
  • dc.relation.projectID info:eu-repo/grantAgreement/H2020/116030
  • dc.rights Copyright © The Author(s) 2021. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword DILI
  • dc.subject.keyword ER stress
  • dc.subject.keyword Mechanism-based risk assessment
  • dc.subject.keyword PHH
  • dc.subject.keyword WGCNA
  • dc.title The human hepatocyte TXG-MAPr: gene co-expression network modules to support mechanism-based risk assessment
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

Col·leccions

Articles (Hospital del Mar Research Institute)
Articles (Departament de Medicina i Ciències de la Vida)