RNA sequencing in human iPSCs derived from bipolar patients to identify important therapeutic molecular targets of Valproate(VPA)
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ABSTRACT:
PROVIDER: PRJNA674370 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12974300.fastq.gz | Fastqsanger.gz | |||
| SRR12974301.fastq.gz | Fastqsanger.gz | |||
| SRR12974302.fastq.gz | Fastqsanger.gz | |||
| SRR12974303.fastq.gz | Fastqsanger.gz | |||
| SRR12974304.fastq.gz | Fastqsanger.gz |
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Project description:Valproate(VPA) has been used in the treatment of bipolar disorder since the 1990s. However, the therapeutic targetsof VPA have remained elusive. Here we used RNA sequencing in human iPSCs derived from bipolar patients to further identify important molecular targets. Human iPSCs were homogenized and total RNA was isolated using the RNeasy Plus Micro Kit (Qiagen, Hilden, Germany). RNA quantity and quality were assessed using fluorometry (Qubit RNA Broad Range Assay Kit and Fluorometer; Invitrogen, Carlsbad, CA) and chromatography (Bioanalyzer and RNA 6000 Nano Kit; Agilent, Santa Clara, CA), respectively. Libraries were prepared using TruSeq Stranded mRNA (PolyA+) kit (Illumina, San Diego, CA) and sequenced by Illumina NextSeq 500. The read length was 75bp with 30-40M reads per sample. FastQC (v0.11.3) was performed to assess data quality. TopHat2 (v2.0.9) aligned the reads to the mouse reference genome (Mus musculus UCSC mm10) and to the Ensembl human reference genome (GRCh38.p13) using default parameters. Alignments were then converted to expression count data using HTseq (v0.6.1) with default union mode.
2020-12-31 | GSE160761 | GEO
Project description:Sodium valproate (VPA) and lithium are mood stabilizers, widely prescribed in the treatment of bipolar disorder, and yet the precise modes of therapeutic action for these drugs are not fully understood. After exposure of the rat serotonergic cell line RN46A to VPA, RNA-sequencing (RNA-Seq) analysis showed widespread changes in gene expression but no changes with lithium. Analysis by multiple pipelines revealed that as many as 230 genes were significantly upregulated and 72 genes were significantly downregulated in response to VPA exposure.
2020-03-07 | GSE146493 | GEO
Project description:Prenatal exposure to the anti-seizure drug sodium valproate (VPA) is associated with an increased risk of adverse postnatal neurodevelopmental outcomes, including lowered intellectual ability, autism spectrum disorder and attention-deficit hyperactivity disorder. In this study, we aimed to clarify the molecular mechanisms underpinning the neurodevelopmental consequences of gestational VPA exposure using integrative genomics. First, we assessed the effect of gestational VPA on fetal brain gene expression using a validated rat model of valproate teratogenicity that mimics the human scenario of chronic oral valproate treatment during pregnancy at doses which are therapeutically relevant to the treatment of epilepsy. Two different rat strains were studied - inbred Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model of genetic generalized epilepsy, and inbred Non-Epileptic Control (NEC) rats. Female rats were fed standard chow or VPA mixed in standard chow for 2 weeks prior to conception and then mated with same-strain males. In the VPA-exposed rats maternal oral treatment was continued throughout pregnancy. Fetuses were extracted via C-section on gestational day 21 (one day prior to birth) and fetal brains were snap frozen and genome-wide gene expression data generated. We found that gestational VPA exposure via chronic maternal oral dosing was associated with substantial drug-induced differential gene expression in the pup brains, including dysregulated splicing, and observed that this occurred in the absence of evidence for significant neuronal gain or loss. The set of genes down-regulated by VPA in the pup brains were significantly enriched for pathways related to neurodevelopment and synaptic function, and significantly enriched for heritability to human intelligence, schizophrenia and bipolar disorder. Our results provide a mechanistic link between chronic fetal VPA exposure and adverse neurodevelopmental outcomes mediated by VPA-induced transcriptional dysregulation.
2022-05-08 | GSE198756 | GEO
Project description:The project had 2 goals: 1) To evaluate the transcriptional response of 3 prototypical toxicants (Clofibrate, VPA, and DEHP) on rat lever. 2) To evaluate the impact pooling samples has on data analysis. Keywords = Clofibrate Keywords = Diethylhexyl phthalate Keywords = Phthalic acid bis(2-ethylhexyl ester) Keywords = Sodium Valproate Keywords = Valproic Acid Keywords = VPA Keywords = vehicle Keywords: other
2005-06-02 | GSE2303 | GEO
Project description:Valproic acid (VPA) is a potent inducer of neural tube defects (NTDs), but its mechanism of teratogenicity is not known. To study the transcriptional response of VPA during the susceptible period, i.e. when VPA is likely to exert most of its teratogenic effect, RNA was extracted from 8.25-dpc embryos (6 h post treatment) from control and VPA-treated dams, and subjected to microarray analysis (four arrays). To be more useful for risk assessment, in vitro models, using cells, may bridge biomarkers discovered by gene expression profiling in an animal in vivo model. Since pluripotent embryocarcinoma (EC) cell lines may be relevant models for early embryonic cells, P19 mouse EC cells were treated with or without 1 mM sodium valproate for 24 h and alos subjected to microarray analysis (four arrays).
2004-08-01 | E-MEXP-45 | biostudies-arrayexpress
Project description:Valproic acid (VPA) is one of the most commonly used anti-epileptic drugs with pharmacological actions on GABA and blocking voltage-gated ion channels. VPA also inhibits histone deacetylase (HDAC) activity. Suberoylanilide hydroxamic acid is also a member of a larger class of compounds that inhibit HDACs. At the time of this article, there are 123 active international clinical trials for VPA (also known as valproate, convulex, divalproex, and depakote) and SAHA (vorinostat, zolinza). While it is well known that VPA and SAHA influence the accumulation of acetylated lysine residues on histones, their true epigenetic complexity remains poorly understood. Primary human cells were exposed to VPA and SAHA to understand the extent of histone acetylation (H3K9/14ac) using chromatin immunoprecipitation followed by sequencing (ChIP-seq). Because histone acetylation is often associated with modification of lysine methylation, we also examined H3K4me3 and H3K9me3. To assess the influence of the HDAC inhibitors on gene expression, we used RNA sequencing (RNA-seq).
2024-09-04 | GSE276338 | GEO
Project description:The antiepileptic drug valproic acid (vpa) is known teratogen giving neural tube defects (ntd:s). Administration of vpa to female NMRI on gestation day 8 induces a high incidence of ntd. In this study we investigate the time dependent gene expression changes induced in the embryo 1.5, 3 respectively 6 hr after maternal sodium valproate treatment.
2008-03-28 | E-MEXP-1062 | biostudies-arrayexpress
Project description:The aim of this study is to determine the efficacy of combining the histone deacetylase (HDAC) inhibitor sodium valproate (VPA) with anti-EGFR monoclonal antibody (panitumumab or cetuximab) maintenance in the first-line treatment of patients with RAS wild type metastatic CRC.
| 5791 | ecrin-mdr-crc
Project description:Studying chemical disturbances during neural differentiation of mES cells has been established as an alternative in vitro testing approach for the identification of developmental toxicants. miRNAs represent a class of small regulatory RNA molecules, which bind to target mRNAs thereby repressing their translation. Many studies have shown an essential role of miRNAs in regulation of gene expression during development and ESC differentiation. Thus, neural differentiation of ESC in vitro allows investigating the role of miRNAs in chemical-mediated developmental toxicity. We analyzed the expression of miRNAs and transcriptomics changes during neural differentiation of mESC exposed to the developmental neurotoxicant sodium valproate (VPA). A total of 110 miRNAs and 377 mRNAs were identified differently expressed in neural differentiating mES cells under VPA treatment (300µM) compared to solvent control on day 16 of differentiation. Analysis of miRNA expression revealed that valproate switches the lineage specification from neural to myogenic differentiation (upregulation of muscle-enriched miRNAs mir-206, mir-133a and mir-10a and downregulation of neuro-specific miRNAs mir-124a, mir-128 and mir-137). The findings on the miRNA level could be confirmed on mRNA level (induction of expression of myogenic regulatory factors (MRFs) as well as muscle specific genes (Actc1, calponin, myosin light chain, asporin, decorin) and repression of genes involved in neurogenesis (Otx1 and 2, Zic3, 4, 5)) as well as morphologically by immunocytochemistry. The observed results were VPA specific and most probably due to inhibition of histone deacetylase (HDAC) activity of VPA for two reasons: (i) we did not observe any induction of muscle specific miRNAs in neural differentiating ES cells exposed to the unrelated developmental neurotoxicant sodium arsenite; (ii) expression of muscle specific mir-206 and muscle enriched mir-10a was similarly increased in cells exposed to a structurally different HDAC inhibitor, trichostatin A (TSA). Furthermore, using our in vitro cell system we could confirm an aberrant expression of known VPA target genes and genes involved in neural tube closure. We conclude that miRNA expression profiling is a suitable molecular endpoint for developmental neurotoxicity. Observed lineage shift into myogenesis, where miRNAs play a significant role, could be a major developmental neurotoxical mechanism of VPA. We used microarray approach to identify altered miRNA expression in neural differentiated mES cells exposed to two known developmental neurotxicants and epigenetic active substances, sodium valproate (VPA) and sodium arsenite (As)
2016-08-01 | GSE50215 | GEO
Project description:Studying chemical disturbances during neural differentiation of mES cells has been established as an alternative in vitro testing approach for the identification of developmental toxicants. miRNAs represent a class of small regulatory RNA molecules, which bind to target mRNAs thereby repressing their translation. Many studies have shown an essential role of miRNAs in regulation of gene expression during development and ESC differentiation. Thus, neural differentiation of ESC in vitro allows investigating the role of miRNAs in chemical-mediated developmental toxicity. We analyzed the expression of miRNAs and transcriptomics changes during neural differentiation of mESC exposed to the developmental neurotoxicant sodium valproate (VPA). A total of 110 miRNAs and 377 mRNAs were identified differently expressed in neural differentiating mES cells under VPA treatment (300µM) compared to solvent control on day 16 of differentiation. Analysis of miRNA expression revealed that valproate switches the lineage specification from neural to myogenic differentiation (upregulation of muscle-enriched miRNAs mir-206, mir-133a and mir-10a and downregulation of neuro-specific miRNAs mir-124a, mir-128 and mir-137). The findings on the miRNA level could be confirmed on mRNA level (induction of expression of myogenic regulatory factors (MRFs) as well as muscle specific genes (Actc1, calponin, myosin light chain, asporin, decorin) and repression of genes involved in neurogenesis (Otx1 and 2, Zic3, 4, 5)) as well as morphologically by immunocytochemistry. The observed results were VPA specific and most probably due to inhibition of histone deacetylase (HDAC) activity of VPA for two reasons: (i) we did not observe any induction of muscle specific miRNAs in neural differentiating ES cells exposed to the unrelated developmental neurotoxicant sodium arsenite; (ii) expression of muscle specific mir-206 and muscle enriched mir-10a was similarly increased in cells exposed to a structurally different HDAC inhibitor, trichostatin A (TSA). Furthermore, using our in vitro cell system we could confirm an aberrant expression of known VPA target genes and genes involved in neural tube closure. We conclude that miRNA expression profiling is a suitable molecular endpoint for developmental neurotoxicity. Observed lineage shift into myogenesis, where miRNAs play a significant role, could be a major developmental neurotoxical mechanism of VPA. We used microarray approach to identify altered miRNA expression in neural differentiated mES cells exposed to two known developmental neurotxicants and epigenetic active substances, sodium valproate (VPA) and sodium arsenite (As) mES cells line W4 were induced to differnetiate into neurons under exposure to VPA for 16 days. RNA for microarrays was collected on day 16 of differentiation from three biological replicates of solvent control (PBS) and VPA treated cells.
2016-08-01 | E-GEOD-50215 | biostudies-arrayexpress