Grouping of histone deacetylase inhibitors and other toxicants disturbing neural crest migration by transcriptional profiling
Grouping of histone deacetylase inhibitors and other toxicants disturbing neural crest migration by transcriptional profiling
Date
2015
Authors
Sügis, Elena
Meisig, Johannes
Blüthgen, Nils
Editors
Journal ISSN
Electronic ISSN
ISBN
Bibliographical data
Publisher
Series
URI (citable link)
DOI (citable link)
International patent number
Link to the license
EU project number
Project
Open Access publication
Collections
Title in another language
Publication type
Journal article
Publication status
Published
Published in
NeuroToxicology ; 50 (2015). - pp. 56-70. - ISSN 0161-813X. - eISSN 1872-9711
Abstract
Functional assays, such as the "migration inhibition of neural crest cells" (MINC) developmental toxicity test, can identify toxicants without requiring knowledge on their mode of action (MoA). Here, we were interested, whether (i) inhibition of migration by structurally diverse toxicants resulted in a unified signature of transcriptional changes; (ii) whether statistically-identified transcript patterns would inform on compound grouping even though individual genes were little regulated, and (iii) whether analysis of a small group of biologically-relevant transcripts would allow the grouping of compounds according to their MoA. We analyzed transcripts of 35 'migration genes' after treatment with 16 migration-inhibiting toxicants. Clustering, principal component analysis and correlation analyses of the data showed that mechanistically related compounds (e.g. histone deacetylase inhibitors (HDACi), PCBs) triggered similar transcriptional changes, but groups of structurally diverse toxicants largely differed in their transcriptional effects. Linear discriminant analysis (LDA) confirmed the specific clustering of HDACi across multiple separate experiments. Similarity of the signatures of the HDACi trichostatin A and suberoylanilide hydroxamic acid to the one of valproic acid (VPA), suggested that the latter compound acts as HDACi when impairing neural crest migration. In conclusion, the data suggest that (i) a given functional effect (e.g. inhibition of migration) can be associated with highly diverse signatures of transcript changes; (ii) statistically significant grouping of mechanistically-related compounds can be achieved on the basis of few genes with small regulations. Thus, incorporation of mechanistic markers in functional in vitro tests may support read-across procedures, also for structurally un-related compounds.
Summary in another language
Subject (DDC)
570 Biosciences, Biology
Keywords
Neural crest, Migration, Read-across, Chemical grouping, Gene expression, HDAC inhibitors, Pesticides, Metals, PCBs, Pathways of toxicity, Toxicology
Conference
Review
undefined / . - undefined, undefined. - (undefined; undefined)
Cite This
ISO 690
DRESER, Nadine, Bastian ZIMMER, Christian DIETZ, Elena SÜGIS, Giorgia PALLOCCA, Johanna NYFFELER, Johannes MEISIG, Nils BLÜTHGEN, Michael R. BERTHOLD, Tanja WALDMANN, Marcel LEIST, 2015. Grouping of histone deacetylase inhibitors and other toxicants disturbing neural crest migration by transcriptional profiling. In: NeuroToxicology. 50, pp. 56-70. ISSN 0161-813X. eISSN 1872-9711. Available under: doi: 10.1016/j.neuro.2015.07.008BibTex
@article{Dreser2015Group-32362, year={2015}, doi={10.1016/j.neuro.2015.07.008}, title={Grouping of histone deacetylase inhibitors and other toxicants disturbing neural crest migration by transcriptional profiling}, volume={50}, issn={0161-813X}, journal={NeuroToxicology}, pages={56--70}, author={Dreser, Nadine and Zimmer, Bastian and Dietz, Christian and Sügis, Elena and Pallocca, Giorgia and Nyffeler, Johanna and Meisig, Johannes and Blüthgen, Nils and Berthold, Michael R. and Waldmann, Tanja and Leist, Marcel} }
RDF
<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bibo="http://purl.org/ontology/bibo/" xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#" xmlns:foaf="http://xmlns.com/foaf/0.1/" xmlns:void="http://rdfs.org/ns/void#" xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > <rdf:Description rdf:about="https://kops.uni-konstanz.de/server/rdf/resource/123456789/32362"> <dc:contributor>Pallocca, Giorgia</dc:contributor> <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/> <dcterms:title>Grouping of histone deacetylase inhibitors and other toxicants disturbing neural crest migration by transcriptional profiling</dcterms:title> <dc:creator>Zimmer, Bastian</dc:creator> <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/> <dc:creator>Nyffeler, Johanna</dc:creator> <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/32362/1/Dreser_0-310991.pdf"/> <dc:contributor>Leist, Marcel</dc:contributor> <dc:creator>Pallocca, Giorgia</dc:creator> <dc:contributor>Sügis, Elena</dc:contributor> <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/32362/1/Dreser_0-310991.pdf"/> <dc:rights>terms-of-use</dc:rights> <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/32362"/> <dc:creator>Leist, Marcel</dc:creator> <dc:creator>Dietz, Christian</dc:creator> <dc:contributor>Waldmann, Tanja</dc:contributor> <foaf:homepage rdf:resource="http://localhost:8080/"/> <dc:contributor>Dietz, Christian</dc:contributor> <dc:contributor>Dreser, Nadine</dc:contributor> <dc:contributor>Blüthgen, Nils</dc:contributor> <dc:creator>Blüthgen, Nils</dc:creator> <dcterms:issued>2015</dcterms:issued> <dcterms:abstract xml:lang="eng">Functional assays, such as the "migration inhibition of neural crest cells" (MINC) developmental toxicity test, can identify toxicants without requiring knowledge on their mode of action (MoA). Here, we were interested, whether (i) inhibition of migration by structurally diverse toxicants resulted in a unified signature of transcriptional changes; (ii) whether statistically-identified transcript patterns would inform on compound grouping even though individual genes were little regulated, and (iii) whether analysis of a small group of biologically-relevant transcripts would allow the grouping of compounds according to their MoA. We analyzed transcripts of 35 'migration genes' after treatment with 16 migration-inhibiting toxicants. Clustering, principal component analysis and correlation analyses of the data showed that mechanistically related compounds (e.g. histone deacetylase inhibitors (HDACi), PCBs) triggered similar transcriptional changes, but groups of structurally diverse toxicants largely differed in their transcriptional effects. Linear discriminant analysis (LDA) confirmed the specific clustering of HDACi across multiple separate experiments. Similarity of the signatures of the HDACi trichostatin A and suberoylanilide hydroxamic acid to the one of valproic acid (VPA), suggested that the latter compound acts as HDACi when impairing neural crest migration. In conclusion, the data suggest that (i) a given functional effect (e.g. inhibition of migration) can be associated with highly diverse signatures of transcript changes; (ii) statistically significant grouping of mechanistically-related compounds can be achieved on the basis of few genes with small regulations. Thus, incorporation of mechanistic markers in functional in vitro tests may support read-across procedures, also for structurally un-related compounds.</dcterms:abstract> <dc:creator>Berthold, Michael R.</dc:creator> <dc:creator>Meisig, Johannes</dc:creator> <dc:contributor>Nyffeler, Johanna</dc:contributor> <dc:creator>Sügis, Elena</dc:creator> <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2015-12-07T15:04:24Z</dc:date> <dc:contributor>Meisig, Johannes</dc:contributor> <dcterms:rights rdf:resource="https://rightsstatements.org/page/InC/1.0/"/> <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/> <dc:creator>Dreser, Nadine</dc:creator> <dc:contributor>Berthold, Michael R.</dc:contributor> <dc:contributor>Zimmer, Bastian</dc:contributor> <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2015-12-07T15:04:24Z</dcterms:available> <dc:creator>Waldmann, Tanja</dc:creator> <dc:language>eng</dc:language> </rdf:Description> </rdf:RDF>
Internal note
xmlui.Submission.submit.DescribeStep.inputForms.label.kops_note_fromSubmitter
Examination date of dissertation
Method of financing
Comment on publication
Alliance license
Corresponding Authors der Uni Konstanz vorhanden
International Co-Authors
Bibliography of Konstanz
Yes