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Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18. doi: 10.1016/j.tiv.2014.12.011. Epub 2015 Jan 13.

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

Author information

1
Department of Physiology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address: alice.limonciel@i-med.ac.at.
2
Emergentec Biodevelopment GmbH, Vienna, Austria.
3
Division of Biostatistics (C060) Medical Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
4
Non-Clinical Safety, Merck Serono, Merck KGaA, Darmstadt, Germany; Institut für Angewandte Biowissenschaften, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
5
KaLy-Cell, Plobsheim, France.
6
Department of Physiology, Medical University of Innsbruck, Innsbruck, Austria.
7
KaLy-Cell, Plobsheim, France; EA4267, Université de Franche-Comté, Besançon, France.
8
Non-Clinical Safety, Merck Serono, Merck KGaA, Darmstadt, Germany.
9
Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, Didcot OX11 0RQ, UK.

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.

KEYWORDS:

Hazard identification; Stress response pathway; Transcription factor; Transcriptomics

PMID:
25596134
DOI:
10.1016/j.tiv.2014.12.011
[Indexed for MEDLINE]

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