title: Transcriptomics hit the target: Monitoring of ligand-activated and stress response pathways for chemical testing.
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.
authors.affiliation: Department of Physiology, Medical University of Innsbruck, Innsbruck, Austria. Electronic address: alice.limonciel@i-med.ac.at.
authors.forename: Alice
authors.initials: A
authors.lastname: Limonciel
authors.affiliation: Emergentec Biodevelopment GmbH, Vienna, Austria.
authors.forename: Konrad
authors.initials: K
authors.lastname: Moenks
authors.affiliation: Division of Biostatistics (C060) Medical Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Stanzel
authors.affiliation: Non-Clinical Safety, Merck Serono, Merck KGaA, Darmstadt, Germany; Institut für Angewandte Biowissenschaften, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
authors.forename: Germaine L
authors.initials: GL
authors.lastname: Truisi
authors.affiliation: KaLy-Cell, Plobsheim, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Parmentier
authors.affiliation: Department of Physiology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Lydia
authors.initials: L
authors.lastname: Aschauer
authors.affiliation: Department of Physiology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Anja
authors.initials: A
authors.lastname: Wilmes
authors.affiliation: KaLy-Cell, Plobsheim, France; EA4267, Université de Franche-Comté, Besançon, France.
authors.forename: Lysiane
authors.initials: L
authors.lastname: Richert
authors.affiliation: Non-Clinical Safety, Merck Serono, Merck KGaA, Darmstadt, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Hewitt
authors.affiliation: Non-Clinical Safety, Merck Serono, Merck KGaA, Darmstadt, Germany; Institut für Angewandte Biowissenschaften, Karlsruhe Institute of Technology (KIT), Karlsruhe, Germany.
authors.forename: Stefan O
authors.initials: SO
authors.lastname: Mueller
authors.affiliation: Emergentec Biodevelopment GmbH, Vienna, Austria.
authors.forename: Arno
authors.initials: A
authors.lastname: Lukas
authors.affiliation: Division of Biostatistics (C060) Medical Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Kopp-Schneider
authors.affiliation: Centre for Radiation, Chemical and Environmental Hazards, Public Health England, Chilton, Didcot OX11 0RQ, UK.
authors.forename: Martin O
authors.initials: MO
authors.lastname: Leonard
authors.affiliation: Department of Physiology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Paul
authors.initials: P
authors.lastname: Jennings
mesh_terms: D000818:Animals; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D016208:Databases, Factual; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D015386:Hazardous Substances / Q000633:toxicity*; D006801:Humans; D008024:Ligands; D020411:Oligonucleotide Array Sequence Analysis; D017422:Sequence Analysis, DNA; D012984:Software; D013312:Stress, Physiological; D014157:Transcription Factors / Q000378:metabolism; D059467:Transcriptome
chemical_list: D015386:Hazardous Substances; D008024:Ligands; D014157:Transcription Factors
keywords: Hazard identification; Stress response pathway; Transcription factor; Transcriptomics