Universität zu Köln

Balmer, Nina V., Klima, Stefanie, Rempel, Eugen, Ivanova, Violeta N., Kolde, Raivo ORCID: 0000-0003-2886-6298, Weng, Matthias K., Meganathan, Kesavan, Henry, Margit, Sachinidis, Agapios, Berthold, Michael R., Hengstler, Jan G., Rahnenfuhrer, Jorg ORCID: 0000-0002-8947-440X, Waldmann, Tanja and Leist, Marcel ORCID: 0000-0002-3778-8693 (2014). From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch. Toxicol., 88 (7). S. 1451 - 1469. HEIDELBERG: SPRINGER HEIDELBERG. ISSN 1432-0738

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Abstract

The superordinate principles governing the transcriptome response of differentiating cells exposed to drugs are still unclear. Often, it is assumed that toxicogenomics data reflect the immediate mode of action (MoA) of drugs. Alternatively, transcriptome changes could describe altered differentiation states as indirect consequence of drug exposure. We used here the developmental toxicants valproate and trichostatin A to address this question. Neurally differentiating human embryonic stem cells were treated for 6 days. Histone acetylation (primary MoA) increased quickly and returned to baseline after 48 h. Histone H3 lysine methylation at the promoter of the neurodevelopmental regulators PAX6 or OTX2 was increasingly altered over time. Methylation changes remained persistent and correlated with neurodevelopmental defects and with effects on PAX6 gene expression, also when the drug was washed out after 3-4 days. We hypothesized that drug exposures altering only acetylation would lead to reversible transcriptome changes (indicating MoA), and challenges that altered methylation would lead to irreversible developmental disturbances. Data from pulse-chase experiments corroborated this assumption. Short drug treatment triggered reversible transcriptome changes; longer exposure disrupted neurodevelopment. The disturbed differentiation was reflected by an altered transcriptome pattern, and the observed changes were similar when the drug was washed out during the last 48 h. We conclude that transcriptome data after prolonged chemical stress of differentiating cells mainly reflect the altered developmental stage of the model system and not the drug MoA. We suggest that brief exposures, followed by immediate analysis, are more suitable for information on immediate drug responses and the toxicity MoA.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Balmer, Nina V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Klima, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Rempel, Eugen UNSPECIFIED UNSPECIFIED UNSPECIFIED Ivanova, Violeta N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kolde, Raivo UNSPECIFIED orcid.org/0000-0003-2886-6298 UNSPECIFIED Weng, Matthias K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Meganathan, Kesavan UNSPECIFIED UNSPECIFIED UNSPECIFIED Henry, Margit UNSPECIFIED UNSPECIFIED UNSPECIFIED Sachinidis, Agapios UNSPECIFIED UNSPECIFIED UNSPECIFIED Berthold, Michael R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hengstler, Jan G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rahnenfuhrer, Jorg UNSPECIFIED orcid.org/0000-0002-8947-440X UNSPECIFIED Waldmann, Tanja UNSPECIFIED UNSPECIFIED UNSPECIFIED Leist, Marcel UNSPECIFIED orcid.org/0000-0002-3778-8693 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-435144
DOI:	10.1007/s00204-014-1279-6
Journal or Publication Title:	Arch. Toxicol.
Volume:	88
Number:	7
Page Range:	S. 1451 - 1469
Date:	2014
Publisher:	SPRINGER HEIDELBERG
Place of Publication:	HEIDELBERG
ISSN:	1432-0738
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EMBRYONIC STEM-CELLS; IN-VITRO TEST; VALPROIC ACID; DEVELOPMENTAL NEUROTOXICITY; GENE-EXPRESSION; DEACETYLASE INHIBITORS; SYSTEMS TOXICOLOGY; DESIGN PRINCIPLES; HUMAN BRAIN; DIFFERENTIATION Multiple languages Toxicology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/43514