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GSE75582
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
- 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- Mus musculus
- 6 Downloadable Samples
- Affymetrix Murine Genome U74A Version 2 Array (mgu74av2)
Description
3 pairs of wt and ClC-6 knockout mice, RNA from p14 hippocampus
Publication Title
Lysosomal storage disease upon disruption of the neuronal chloride transport protein ClC-6.
Sample Metadata Fields
Sex, Age, Specimen part, Subject, Time
View Samples- Mus musculus
- 10 Downloadable Samples
Illumina HiSeq 2500
Description
The histone variant H3.3 is incorporated in a replication-independent manner at heterochromatic regions by the ATRX-DAXX histone chaperone complex. Here, we present a high-resolution x-ray crystal structure of an interaction surface between ATRX and DAXX. We used single amino acid substitutions in DAXX that abrogate formation of the complex to explore ATRX-dependent and -independent functions of DAXX. We found that the repression of specific murine endogenous retroviruses is dependent on DAXX, but not on ATRX. In support, we reveal the existence of two biochemically distinct DAXX-containing complexes: The ATRX-DAXX complex involved in gene repression and telomere chromatin structure, and a DAXX-SETDB1-KAP1-HDAC1 complex that represses endogenous retroviruses independently of ATRX and H3.3 incorporation into chromatin. We found that histone H3.3 stabilizes DAXX protein levels and affects DAXX-regulated genes independently of its incorporation into nucleosomes. Our findings represent the first description of a nucleosome-independent function for the H3.3 histone variant. Overall design: RNA-seq analysis of five embryonic stem cell lines in duplicate (Daxx-/- mESC, Daxx-/- mESC rescued with Daxx WT, H3.3 KO mESC, H3.3 KO mESC rescued with H3.3 WT and H3.3 L126A-L130A mutant)
Publication Title
Structural and mechanistic insights into ATRX-dependent and -independent functions of the histone chaperone DAXX.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 7 Downloadable Samples
- Affymetrix Mouse Expression 430A Array (moe430a)
Description
Inducible co-stimulator (ICOS) interaction with its ligand (ICOSL) is involved in several T cell effector functions. While blockade of ICOS:ICOSL interaction in chronic graft versus host disease (GVHD) seems benefi cial, results for acute GVHD remain controversial. To further elucidate its role in acute GVHD, C57BL / 6 mice were lethally irradiated and reconstituted with allogeneic spleen cells in the absence or presence of ICOSL-blocking mAb. Mice reconstituted with allogeneic spleen cells experienced severe GVHD and died untreated within 6 9 days after transplantation. Mice treated with an anti-ICOSL mAb starting from day 3 after transplantation gained weight again and survived for at least additional 12 days, although the treatment was already stopped at day 11 after transplantation. In contrast, the anti-ICOSL treatment starting from day 0 did not prevent GVHD. The diff erence between therapeutic (day 3) and prophylactic (day 0) anti-ICOSL treatment was independent of CD25 + CD4 + regulatory T cells since their depletion did not abrogate the therapeutic eff ect of ICOSL blockade. Microarray analysis revealed IFN- and chemokine up-regulation in spleen cells of prophylactically treated mice, emphasizing kinetic dependence of acute GVHD modulation via blockade of ICOS:ICOSL interaction.
Publication Title
Only therapeutic ICOS:ICOSL blockade alleviates acute graft versus host disease.
Sample Metadata Fields
Sex, Specimen part
View Samples- Rattus norvegicus
- 8 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Polycystic ovarian syndrome (PCOS) is an endocrine disorder of the reproductive and metabolic axis in women during the reproductive age. In this study, we used a rat model exhibiting reproductive and metabolic abnormalities similar to human PCOS to unravel the molecular mechanisms underlining this complex syndrome.
Publication Title
Polycystic ovarian syndrome is accompanied by repression of gene signatures associated with biosynthesis and metabolism of steroids, cholesterol and lipids.
Sample Metadata Fields
Specimen part
View Samples- Bos taurus
- 12 Downloadable Samples
- Affymetrix Bovine Genome Array (bovine)
Description
Aberrant placental gene expression associated with culture condition and/or deficiencies in transcriptome reprogramming are hypothesized to be the major cause of SCNT and IVP inefficiencies. Therefore, the main objective of this study was to invesitgate the dysregulated genes, molecular pathways and functional alteration in bovine placentas derived from SCNT and IVP pregnancies compared to their AI counterparts
Publication Title
Aberrant placenta gene expression pattern in bovine pregnancies established after transfer of cloned or in vitro produced embryos.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Sus scrofa
- 18 Downloadable Samples
- Porcine Gene 1.0 ST Array (porgene10st)
Description
In vivo microarray study of global gene expression changes in peripheral blood mononuclear cells (PBMCs) of Pietrain pigs during the stage of inatte immune and adaptive immune response to porcine reproductive and respiratory syndrome virus vaccination.
Publication Title
PBMC transcriptome profiles identifies potential candidate genes and functional networks controlling the innate and the adaptive immune response to PRRSV vaccine in Pietrain pig.
Sample Metadata Fields
Sex
View Samples- Homo sapiens
- 14 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
GEP on Affymetrix U133+2.0 microarrays was performed on ex vivo cell-sorted Tfh from FL or TONS
Publication Title
CD10 delineates a subset of human IL-4 producing follicular helper T cells involved in the survival of follicular lymphoma B cells.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2000
Description
We report pregnacy-induced changes at the RNA level using RNAseq Overall design: Comparison of RNA transcript of islets isolated from 5 control and 5 pregnant animals at gestational day 14.5
Publication Title
Research Resource: A Dual Proteomic Approach Identifies Regulated Islet Proteins During β-Cell Mass Expansion In Vivo.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples