title: Neuronal developmental gene and miRNA signatures induced by histone deacetylase inhibitors in human embryonic stem cells.
abstract: Human embryonic stem cells (hESCs) may be applied to develop human-relevant sensitive in vitro test systems for monitoring developmental toxicants. The aim of this study was to identify potential developmental toxicity mechanisms of the histone deacetylase inhibitors (HDAC) valproic acid (VPA), suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) relevant to the in vivo condition using a hESC model in combination with specific differentiation protocols and genome-wide gene expression and microRNA profiling. Analysis of the gene expression data showed that VPA repressed neural tube and dorsal forebrain (OTX2, ISL1, EMX2 and SOX10)-related transcripts. In addition, VPA upregulates axonogenesis and ventral forebrain-associated genes, such as SLIT1, SEMA3A, DLX2/4 and GAD2. HDACi-induced expression of miR-378 and knockdown of miR-378 increases the expression of OTX2 and EMX2, which supports our hypothesis that HDACi targets forebrain markers through miR-378. In conclusion, multilineage differentiation in vitro test system is very sensitive for monitoring molecular activities relevant to in vivo neuronal developmental toxicity. Moreover, miR-378 seems to repress the expression of the OTX2 and EMX2 and therefore could be a regulator of the development of neural tube and dorsal forebrain neurons.
authors.affiliation: Center of Physiology and Pathophysiology, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Robert-Koch-Str. 39, Cologne, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Meganathan
authors.affiliation: Center of Physiology and Pathophysiology, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Robert-Koch-Str. 39, Cologne, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Jagtap
authors.affiliation: Center of Physiology and Pathophysiology, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Robert-Koch-Str. 39, Cologne, Germany.
authors.forename: S P
authors.initials: SP
authors.lastname: Srinivasan
authors.affiliation: Center of Physiology and Pathophysiology, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Robert-Koch-Str. 39, Cologne, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Wagh
authors.affiliation: Center of Physiology and Pathophysiology, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Robert-Koch-Str. 39, Cologne, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hescheler
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors, Technical University of Dortmund (IfADo), Dortmund, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hengstler
authors.affiliation: Doerenkamp-Zbinden Chair for In Vitro Toxicology and Biomedicine, University of Konstanz, Konstanz, Germany.
authors.forename: M
authors.identifier: 0000000237788693
authors.initials: M
authors.lastname: Leist
authors.affiliation: Center of Physiology and Pathophysiology, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Robert-Koch-Str. 39, Cologne, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Sachinidis
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects; D055106:Genome-Wide Association Study; D056572:Histone Deacetylase Inhibitors / Q000633:toxicity*; D000066449:Human Embryonic Stem Cells / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects* / Q000235:genetics; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D018675:Toxicity Tests / Q000379:methods
chemical_list: D056572:Histone Deacetylase Inhibitors; D035683:MicroRNAs