RNA-seq of Primary Human Hepatocytes (PHH) exposed to Valproic Acid (VPA) for 3 days daily and 3 days daily exposure followed by 3 days washout.
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina HiSeq 2500
ORGANISM(S): Homo sapiens
SUBMITTER: Jarno Wolters
PROVIDER: E-MTAB-5984 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:Primary Human Hepatocytes (PHH) were exposed daily for 3 days to 15 mM VPA after which DNA was isolated. After terminating the VPA treatment, part of the cells were kept with medium for 3 days in order to investigate the eventual persistence of VPA-induced methylome changes. Identification of methylated regions in the DNA was carried out by the Methylated DNA Immuno-Precipitation - sequencing (MeDIP-seq) method and contains the following steps: fragmentation, library preparation, MeDIP, and sequencing.
2018-02-23 | E-MTAB-5983 | biostudies-arrayexpress
Project description:Primary Human Hepatocytes (PHH) were exposed daily for 5 days to 15 mM VPA after which DNA was isolated. After terminating the VPA treatment, part of the cells were kept with medium for 3 days in order to investigate the eventual persistence of VPA-induced methylome changes. Identification of methylated regions in the DNA was carried out by the Methylated DNA Immuno-Precipitation - sequencing (MeDIP-seq) method and contains the following steps: fragmentation, library preparation, MeDIP, and sequencing.
2017-09-25 | E-MTAB-4437 | biostudies-arrayexpress
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 to neurons under exposure to VPA and As for 16 days. RNA for microarrays was collected on day 16 of differentiation from three biological replicates of solvent controls (PBS was used as a solvent for VPA and H20 for As) or substance treated cells.
2016-08-01 | E-GEOD-50216 | biostudies-arrayexpress
Project description:Rett syndrome (RTT) is a devastating neurodevelopmental disorder that occurs once in every 10,000-15,000 live female births. Despite intensive research, no effective cure is yet available. Valproic acid (VPA) has been used widely to treat mood disorder, epilepsy, and a growing number of other disorders. In limited clinical studies, VPA has also been used to control seizure in RTT patients with promising albeit somewhat unclear efficacy. In this study we tested the effect of VPA on the neurological symptoms of RTT and discovered that short-term VPA treatment during the symptomatic period could reduce neurological symptoms in RTT mice. We found that VPA restores the expression of a subset of genes in RTT mouse brains, and these genes clustered in neurological disease and developmental disorder networks. Our data suggest that VPA could be used as a drug to alleviate RTT symptoms. Wild type or MeCP2KO mice received daily injections of VPA (300 mg/kg) for 2 weeks. Each experimental condition: WT control, KO treated with VPA (KO+VPA), and KO treated with saline (KO+saline). Half brain samples were retrieved.
2014-10-04 | E-GEOD-56780 | biostudies-arrayexpress
Project description:Suberoylanilide hydroxamic acid (SAHA) and valproic acid (VPA ) are both histone deacetylases inhibitor (HDACi), and are able to attenuate the activation of hepatic stelllate cells. To explore the underlying molecular mechanisms, we performed miRNA expression profile analyses of human hepatic stellate cell line LX2 treated with SAHA or VPA for 24 hours. Duplicate experiments were performed: Untreated LX2, SAHA treated LX2 and VPA treated LX2.
2019-07-20 | E-MTAB-6752 | biostudies-arrayexpress
Project description:For the purpose of mechanism-based risk assessment, we investigated temporal concentration-dependent responses in cultures of PHH and HepaRG cells exposed to three drugs, acetaminophen (APAP), cyclosporine A (CSA) and valproic acid (VPA), that have a high liability for drug-induced liver injury. To facilitate the identification of early KEs and visualisation of their development over time, samples were collected at 4 time points, namely 8 and 24 hours (single exposure), 48 and 72 hours (daily repeated exposure), after exposure to a broad concentration range. Concentrations were selected based on the reported total Cmax of each drug. As these are approved drugs currently on the market, they are not expected to induce overt adverse effects around Cmax. Therefore, the selected maximum concentration was set at approximately 30x Cmax, whilst the minimum tested concentration was approximately 0.1x Cmax. The large concentration range allowed to apply benchmark concentration (BMC) modelling on individual genes as well as gene co-expression networks to derive in vitro transcriptomics benchmark concentrations (BMCs) and assess their suitability to be used as PoD in chemical risk assessment.
2024-03-01 | E-MTAB-12668 | biostudies-arrayexpress
Project description:Epigenetic code modifications by histone deacetylase inhibitors (HDACi) have recently been proposed as potential new therapies for hematological malignancies. Chronic Lymphocytic Leukemia (CLL) remains incurable despite the introduction of new treatments. CLL cells are characterized by an apoptosis defect rather than excessive proliferation, but proliferation centers have been found in organs such as bone marrow and lymph nodes. Here, we investigated gene expression modifications in CLL cells following treatment with valproic acid (VPA), a well-tolerated anti-epileptic drug with HDAC inhibitory activity. Experiment Overall Design: CLL cells obtained from 14 patients were treated in vitro with a concentration of 1mM VPA for 4 hours. VPA effects on gene expression were thereafter studied using Affymetrix technology
2009-09-17 | E-GEOD-14973 | biostudies-arrayexpress
Project description:Histone deacetylase (HDAC) inhibitors are widely utilized in hematopoietic malignance therapy; nevertheless, little is currently known concerning their effects on normal myelopoiesis. In order to investigate a putative interference of HDAC inhibitors in myeloid commitment of hematopoietic stem/progenitor cells (HSPCs) we treated CD34+ cells with valproic acid (VPA). Moreover, we investigate changes in gene expression induced by VPA treatment on HSPCs, by means of microarray analysis in VPA treated and untreated (CTR) CD34+ cells. VPA treatment induced H4 histone acetylation in CD34+ cells and blocked them in G0-G1 phase of cell cycle. CD34 expression is maintained for a longer time in VPA treated cells, while the physiological decrease of CD34 antigen occurred in CTR cells. Moreover, VPA favored erythrocyte and megakaryocyte differentiation at the expense of granulocyte and mono-macrophage lineages, as demonstrated by immunophenotyping, morphological and clonogenic analysis. Finally, we demonstrated that VPA up-regulated master gene regulators of erythrocyte and megakaryocyte differentiation (GFI1B and MLLT3) through histone iper-acetylation of their promoters. These results indicate that VPA treatment enhances erythrocyte and megakaryocyte differentiation at the expense of granulocyte and mono-macrophage one. Microarray data provide for the first time a detailed molecular support for the biological effects promoted by VPA treatment in HSPCs. Human CD34+ cells were purified from umbilical Cord Blood (CB) samples. After an initial 24 hours of incubation, CD34+ cells were exposed to VPA. Total cellular RNA was extracted from untreated (CTR) and VPA treated CD34+ HSCs after 48 hours of treatment.
2013-04-11 | E-GEOD-31283 | biostudies-arrayexpress
Project description:Approximately 50% of patients with chronic hepatitis C (CHC) have a sustained virologic response (SVR) to treatment with pegylated interferon (pegINF)-α and ribavirin. Non-response to treatment is associated with constitutively increased expression of IFN-stimulated genes (ISGs) in the liver. Treatment of patients with acute hepatitis C (AHC) is more effective, with SVR rates >90%. We investigated mechanisms of the different responses of patients with CHC and AHC to pegIFN-α therapy. We analyzed IFN signaling and ISG expression in liver samples from patients with acute hepatitis C (AHC), patients with chronic hepatitis (CHC), and individuals without hepatitis C (controls) using microarray, immunohistochemical, and protein analyses. Findings were compared with those from primary human hepatocytes stimulated with IFN-α or IFN-γ, as reference sets. Expression levels of 100s of genes, primarily those regulated by IFN-γ, were altered in liver samples from patients with AHC compared with controls. Expression of IFN-γ–stimulated genes was induced in liver samples from patients with AHC, whereas expression of IFN-α–stimulated genes was induced in samples from patients with CHC. In an expression analysis of negative regulators of IFN-α signaling, we did not observe differences in expression of SOCS1 or SOCS3 between liver samples from patients with AHC and those with CHC. However, USP18 (another negative regulator of IFN-α signaling), was upregulated in liver samples of patients with CHC that did not respond to therapy, but not in AHC. In conclusion, differences in expression of ISGs might account for the greater response of patients with AHC, compared to those with CHC, to treatment with pegINF-α and ribavirin. Specifically, USP18 is upregulated in liver samples of patients with CHC that do not respond to therapy, but not in patients with AHC. (Interferon-γ Stimulated Genes, but not USP18, are Expressed in Livers of Patients with Acute Hepatitis C; Dill MT, Makowska Z et al, Gastroenterology 2012 (in press)) Primary human hepatocytes from 2 donors were analyzed. From each donor there are 5 samples: untreated cells, cells treated with interferon alpha (1000 IU/ml) for 6 and 24 hours and cells treated with interferon gamma (1000 IU/ml) for 6 and 24 hours.
2012-06-08 | E-GEOD-38147 | biostudies-arrayexpress
Project description:Accumulating evidences suggest that various epigenetic aberrations play definite roles in the pathogenesis of endometriosis. The aim of this study is to identify 1) the panel of aberrantly expressed genes that are epigenetically suppressed by histone acetylation in endometriosis; 2) the roles of CCAAT/enhancer-binding protein (C/EBP) alpha, one of the candidate molecules whose expression was epigenetically repressed in endometriotic cyst stromal cells (ECSCs), in the pathogenesis of endometriosis; and 3) the efficacy of the histone deacetylase inhibitors for the treatment of endometriosis. Subconfluent ECSCs cultured in 10-cm dish were further incubated for 72 h with or without VPA (8 mM) and/or 5aza. Total RNA from untreated ECSCs (n=4), VPA-treated ECSCs (n=4), 5aza-treated ECSCs (n=4), and VPA- and 5aza-treated ECSCs (n=4) was extracted and subjected to gene expression microarray analysis.
2013-10-21 | E-GEOD-44207 | biostudies-arrayexpress