Transcriptomics hit the target: Monitoring of ligand-activated and stress response pathways for chemical testing

Alice Limonciel*, Konrad Moenks, Sven Stanzel, Germaine L. Truisi, Céline Parmentier, Lydia Aschauer, Anja Wilmes, Lysiane Richert, Philip Hewitt, Stefan O. Mueller, Arno Lukas, Annette Kopp-Schneider, Martin Leonard, Paul Jennings

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Citations (Scopus)

Abstract

High content omic methods provide a deep insight into cellular events occurring upon chemical exposure of a cell population or tissue. However, this improvement in analytic precision is not yet matched by a thorough understanding of molecular mechanisms that would allow an optimal interpretation of these biological changes. For transcriptomics (TCX), one type of molecular effects that can be assessed already is the modulation of the transcriptional activity of a transcription factor (TF). As more ChIP-seq datasets reporting genes specifically bound by a TF become publicly available for mining, the generation of target gene lists of TFs of toxicological relevance becomes possible, based on actual protein-DNA interaction and modulation of gene expression. In this study, we generated target gene signatures for Nrf2, ATF4, XBP1, p53, HIF1a, AhR and PPAR gamma and tracked TF modulation in a large collection of in vitro TCX datasets from renal and hepatic cell models exposed to clinical nephro- and hepato-toxins. The result is a global monitoring of TF modulation with great promise as a mechanistically based tool for chemical hazard identification.

Original languageEnglish
Pages (from-to)7-18
Number of pages12
JournalToxicology in Vitro
Volume30
Issue number1
DOIs
Publication statusPublished - 25 Dec 2015

Bibliographical note

Funding Information:
This project was funded by the European Union’s 7th Framework Programme (FP7/2007-2013) under grant agreement n° 202222, Predict-IV. This work was also financially supported by the European Union FP7/Cosmetics Europe project DETECTIVE, grant agreement n° 266838. Tissue resections for primary human hepatocyte isolation were provided by Bruno Heyd (EA4267 Université de Franche-Comté, Besançon, France; CHR Besançon, France) and Philippe Bachellier (EA4267 Université de Franche-Comté, Besançon, France; Hôpital de Hautepierre, Strasbourg, France).

Publisher Copyright:
© 2014 Elsevier Ltd.

Keywords

  • Hazard identification
  • Stress response pathway
  • Transcription factor
  • Transcriptomics

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