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GSE99861
Homo sapiens
12 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
EDI3 was shown to be relevant in cell migration, adhesion and spreading. Gene expression analysis was performed to determine the effect of EDI3 silencing in MCF7 cells in order to gain insight into potential underlying mechanisms.
Publication Title
EDI3 links choline metabolism to integrin expression, cell adhesion and spreading.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 57 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The in vitro test battery of the European research consortium ESNATS (novel stem cell-based test systems) has been used to screen for potential human developmental toxicants. As part of this effort, the migration of neural crest (MINC) assay has been used to evaluate chemical effects on neural crest function. It identified some drug-like compounds in addition to known environmental toxicants. The hits included the HSP90 inhibitor geldanamycin, the chemotherapeutic arsenic trioxide, the flame-retardant PBDE-99, the pesticide triadimefon and the histone deacetylase inhibitors valproic acid and trichostatin A. Transcriptome changes triggered by these substances in human neural crest cells were recorded and analysed here to answer three questions: (1) can toxicants be individually identified based on their transcript profile; (2) how can the toxicity pattern reflected by transcript changes be compacted/ dimensionality-reduced for practical regulatory use; (3) how can a reduced set of biomarkers be selected for large-scale follow up? Transcript profiling allowed clear separation of different toxicants and the identification of toxicant types in a blinded test study. We also developed a diagrammatic system to visualize and compare toxicity patterns of a group of chemicals by giving a quantitative overview of altered superordinate biological processes (e.g. activation of KEGG pathways or overrepresentation of gene ontology terms). The transcript data were mined for potential markers of toxicity, and 39 transcripts were selected to either indicate general developmental toxicity or distinguish compounds with different modes-of-action in read-across. In summary, we found inclusion of transcriptome data to largely increase the information from the MINC phenotypic test.
Publication Title
Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
TGR5 (Gpbar1) is a G protein-coupled receptor responsive to bile acids (BAs), which is expressed in different non-parenchymal cells of the liver, including biliary epithelial cells, liver-resident macrophages, sinusoidal endothelial cells (LSECs) and activated hepatic stellate cells (HSCs). Mice with targeted deletion of TGR5 are more susceptible towards cholestatic liver injury induced by cholic acid-feeding and bile duct ligation, resulting in a reduced proliferative response and increased liver injury. Conjugated lithocholic acid (LCA) represents the most potent TGR5 BA ligand and LCA-feeding has been used as a model to rapidly induce severe cholestatic liver injury in mice. Thus, TGR5 knockout (KO) mice and wildtype littermates were fed a diet supplemented with 1%LCA for 84 hours. Liver injury and gene expression changes induced by the LCA-diet revealed an enrichment of pathways associated with inflammation, proliferation and matrix remodelling. Knockout of TGR5 in mice caused upregulation of endothelin-1 (ET-1) expression in the livers. Analysis of TGR5-dependent ET-1 signalling in isolated LSECs and HSCs demonstrated that TGR5 activation reduces ET-1 expression and secretion from LSECs and triggers internalization of the ET-1 receptor in HSCs dampening ET-1 responsiveness. Thus, we identified two independent mechanisms by which TGR5 inhibits ET-1 signalling and modulates portal pressure.
Publication Title
The G Protein-Coupled Bile Acid Receptor TGR5 (Gpbar1) Modulates Endothelin-1 Signaling in Liver.
Sample Metadata Fields
Sex
View Samples- Homo sapiens
- 18 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Safety sciences and the identification chemical hazard have been seen as one of the most immediate practical applications of human pluripotent stem cell technology. Protocols for the generation of many desirable human cell types have been developed, but optimization of neuronal models for toxicological use has been astonishingly slow, and the wide, clinically- important field of peripheral neurotoxicity is still largely unexplored. Here, a 2-step protocol to generate large lots of identical peripheral human neuronal precursors was characterized and adapted to the measurement of peripheral neurotoxicity. High content imaging allowed an unbiased assessment of cell morphology and viability. The computational quantification of neurite growth as functional parameter highly sensitive to disturbances by toxicants was used as endpoint reflecting specific neurotoxicity. The differentiation of cells towards dorsal root ganglia neurons was tracked in relation to a large background data set based on gene expression microarrays. On this basis, a peripheral neurotoxicity (PeriTox) test was developed as first toxicological assay that harnesses the potential of human pluripotent stem cells to generate cell types/tissues that are not otherwise available for prediction of human systemic organ toxicity. Testing of more than 30 chemicals showed that human neurotoxicants, as well as neurite growth enhancers, were correctly identified. Various classes of chemotherapeutics causing human peripheral neuropathies were identified, while they were missed when tested on human central neurons. The PeriTox-test established here shows the potential of human stem cells for clinically-relevant safety testing of drugs in use and of new emerging candidates.
Publication Title
Stem Cell-Derived Immature Human Dorsal Root Ganglia Neurons to Identify Peripheral Neurotoxicants.
Sample Metadata Fields
Sex, Specimen part, Cell line
View Samples- Homo sapiens
- 195 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Background: Global gene expression profiling has been widely used in lung cancer research to identify clinically relevant molecular subtypes as well as to predict prognosis and therapy response. So far, the value of these multi-gene signatures in clinical practice is unclear and the biological importance of individual genes is difficult to assess as the published signatures virtually do not overlap.
Publication Title
Biomarker discovery in non-small cell lung cancer: integrating gene expression profiling, meta-analysis, and tissue microarray validation.
Sample Metadata Fields
Sex, Age
View Samples- Homo sapiens
- 82 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Test systems to identify developmental toxicants are urgently needed. A combination of human stem cell technology and transcriptome analysis was used here to provide proof-of-concept that toxicants with a related mode of action can be identified, and grouped for read-across. We chose a test system of developmental toxicity, related to the generation of neuroectoderm from pluripotent stem cells (UKN1), and exposed cells for six days to benchmark concentration (BMC) of histone deacetylase inhibitors (HDACi) valproic acid, trichostatin-A, vorinostat, belinostat, panobinostat and entinostat. To provide insight into their toxic action, we identified HDACi consensus genes, assigned them to superordinate biological processes, and mapped them to a human transcription factor network constructed from hundreds of transcriptome data sets. We also tested a heterogeneous group of mercurials (methylmercury, thimerosal, mercury(II)chloride, mercury(II)bromide, 4-chloromercuribenzoic acid, phenylmercuric acid) (BMCs). Microarray data were compared at the highest non-cytotoxic concentration for all 12 toxicants. A support vector machine (SVM)-based classifier predicted all HDACi correctly. For validation, the classifier was applied to legacy data sets of HDACi, and for each exposure situation, the SVM predictions correlated with the developmental toxicity. Finally, optimization of the classifier based on 100 probe sets showed that eight genes (F2RL2, TFAP2B, EDNRA, FOXD3, SIX3, MT1E, ETS1, LHX2) are sufficient to separate HDACi from mercurials. Our data demonstrate, how human stem cells and transcriptome analysis can be combined for mechanistic grouping and prediction of toxicants. Extension of this concept to mechanisms beyond HDACi would allow prediction of human developmental toxicity hazard of unknown compounds with the UKN1 test system.
Publication Title
A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 15 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
GPAM is well characterized in triglyceride synthesis, but has never been implicated in cancer. Our study report a role for GPAM in cell migration. Gene expression changes after GPAM silencing was investigated to gain insight into possible mechanisms underlying GPAM's role in cell migration.
Publication Title
Glycerol-3-phosphate Acyltransferase 1 Promotes Tumor Cell Migration and Poor Survival in Ovarian Carcinoma.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 148 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The first in vitro tests for developmental toxicity made use of rodent cells. Newer teratology tests, e.g. developed during the ESNATS project, use human cells and measure mechanistic endpoints (such as transcriptome changes). However, the toxicological implications of mechanistic parameters are hard to judge, without functional/morphological endpoints. To address this issue, we developed a new version of the human stem cell-based test STOP-tox(UKN). For this purpose, the capacity of the cells to self-organize to neural rosettes was assessed as functional endpoint: pluripotent stem cells were allowed to differentiate to neuroepithelial cells for six days in the presence or absence of toxicants. Then, both transcriptome changes were measured (standard STOP-tox(UKN)), and cells were allowed to form rosettes. After optimization of staining methods, an imaging algorithm for rosette quantification was implemented and used for an automated rosette formation assay (RoFA). Neural tube toxicants (like valproic acid), which are known to disturb human development at stages when rosette-forming cells are present, were used as positive controls. Established toxicants led to distinctly different tissue organization and differentiation stages. RoFA outcome and transcript changes largely correlated concerning (i) the concentration-dependence, (ii) the time-dependence, and (iii) the set of positive hits identified amongst 24 potential toxicants. Using such comparative data, a prediction model for the RoFA was developed. The comparative analysis was also used to identify gene dysregulations that are particularly predictive for disturbed rosette formation. This ‘RoFA predictor gene set’ may be used for a simplified and less costly setup of the STOP-tox(UKN) assay.
Publication Title
Development of a neural rosette formation assay (RoFA) to identify neurodevelopmental toxicants and to characterize their transcriptome disturbances.
Sample Metadata Fields
Sex, Specimen part, Cell line, Treatment
View Samples- Rattus norvegicus
- 47 Downloadable Samples
IlluminaHiSeq2500
Description
We identified 271 transcripts as differentially regulated in the dorsal raphe and/or the amygdala of high-responder and low-responder rats Overall design: Counts of transcripts (n=6/brain region/strain) from two brain regions (dorsal raphe and amygdala) from rat strains selectively-bred for response to novelty (high-responder/low-responder rats)
Publication Title
Differential stress induced c-Fos expression and identification of region-specific miRNA-mRNA networks in the dorsal raphe and amygdala of high-responder/low-responder rats.
Sample Metadata Fields
No sample metadata fields
View Samples- Caenorhabditis elegans
- 6 Downloadable Samples
- Illumina Genome Analyzer II
Description
Caenorhabditis elegans is one of the most prominent model systems to study embryogenesis. However, it has been impractical to collect large amounts of precisely staged embryos. Thus, early C. elegans embryogenesis has not been amenable to most modern high-throughput genomics or biochemistry assays. To overcome this problem, we devised a method to collect large amounts of cleanly staged C. elegans embryos by Fluorescent Activated Cell Sorting (termed eFACS). eFACS can in principle be applied to all embryonic developmental stages up to hatching. As a proof of principle we show that a single eFACS run routinely yields tens of thousands of almost perfectly staged one-cell embryos. Since in animals the earliest embryonic events are driven by post-transcriptional regulation, we combined eFACS with next-generation sequencing technology to systematically profile the embryonic expression of small, non-coding RNAs. We discovered a wealth of complex and orchestrated changes in the expression between and within almost all classes of small RNAs, including miRNAs, during embryogenesis. Our data indicate that half of all known miRNAs are already expressed in the one-cell stage embryo and we also shed light on the expression and genomic organization of the previously under-appreciated 26G-RNAs. Together, our eFACS data suggest that the complexity of small RNA expression dynamics in animals is comparable to the expression dynamics of protein encoding genes. Overall design: Various C. elegans embryo samples were generated: mixed embryos by traditional bleaching (Brenner, 1974), early embryos by eFACS (Stoeckius et al., in press). RNA was extracted and length fractionated. Small RNA was subjected to a 5''-dependent ligation protocol to add sequencing adapters. The small RNA samples were sequenced using the Illumina GA I & II.
Publication Title
Large-scale sorting of C. elegans embryos reveals the dynamics of small RNA expression.
Sample Metadata Fields
Cell line, Subject
View Samples