Neuronal developmental gene and miRNA signatures induced by histone deacetylase inhibitors in human embryonic stem cells. 2015

K Meganathan, and S Jagtap, and S P Srinivasan, and V Wagh, and J Hescheler, and J Hengstler, and M Leist, and A Sachinidis
Center of Physiology and Pathophysiology, Institute of Neurophysiology and Center for Molecular Medicine Cologne (CMMC), Robert-Koch-Str. 39, Cologne, Germany.

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.

UI MeSH Term Description Entries
D009474 Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM. Nerve Cells,Cell, Nerve,Cells, Nerve,Nerve Cell,Neuron
D002454 Cell Differentiation Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs. Differentiation, Cell,Cell Differentiations,Differentiations, Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000066449 Human Embryonic Stem Cells A type of PLURIPOTENT STEM CELLS derived from early stage human embryos, up to and including the BLASTOCYST stage. hESC,Cells, Human Embryonic Stem,Human Embryonic Stem Cell,Stem Cells, Human Embryonic,hESCs
D055106 Genome-Wide Association Study An analysis comparing the allele frequencies of all available (or a whole GENOME representative set of) polymorphic markers to identify gene candidates or quantitative trait loci associated with a specific organism trait or specific disease or condition. Genome Wide Association Analysis,Genome Wide Association Study,GWA Study,Genome Wide Association Scan,Genome Wide Association Studies,Whole Genome Association Analysis,Whole Genome Association Study,Association Studies, Genome-Wide,Association Study, Genome-Wide,GWA Studies,Genome-Wide Association Studies,Studies, GWA,Studies, Genome-Wide Association,Study, GWA,Study, Genome-Wide Association
D055495 Neurogenesis Formation of NEURONS which involves the differentiation and division of STEM CELLS in which one or both of the daughter cells become neurons. Neurogeneses
D056572 Histone Deacetylase Inhibitors Compounds that inhibit HISTONE DEACETYLASES. This class of drugs may influence gene expression by increasing the level of acetylated HISTONES in specific CHROMATIN domains. HDAC Inhibitor,HDAC Inhibitors,Histone Deacetylase Inhibitor,Deacetylase Inhibitor, Histone,Deacetylase Inhibitors, Histone,Inhibitor, HDAC,Inhibitor, Histone Deacetylase,Inhibitors, HDAC,Inhibitors, Histone Deacetylase
D018675 Toxicity Tests An array of tests used to determine the toxicity of a substance to living systems. These include tests on clinical drugs, foods, and environmental pollutants. Tests, Toxicity,Test, Toxicity,Toxicity Test
D035683 MicroRNAs Small double-stranded, non-protein coding RNAs, 21-25 nucleotides in length generated from single-stranded microRNA gene transcripts by the same RIBONUCLEASE III, Dicer, that produces small interfering RNAs (RNA, SMALL INTERFERING). They become part of the RNA-INDUCED SILENCING COMPLEX and repress the translation (TRANSLATION, GENETIC) of target RNA by binding to homologous 3'UTR region as an imperfect match. The small temporal RNAs (stRNAs), let-7 and lin-4, from C. elegans, are the first 2 miRNAs discovered, and are from a class of miRNAs involved in developmental timing. RNA, Small Temporal,Small Temporal RNA,miRNA,stRNA,Micro RNA,MicroRNA,Primary MicroRNA,Primary miRNA,miRNAs,pre-miRNA,pri-miRNA,MicroRNA, Primary,RNA, Micro,Temporal RNA, Small,miRNA, Primary,pre miRNA,pri miRNA

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