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Mus musculus
88 Downloadable Samples
Affymetrix HT MG-430 PM Array Plate (htmg430pm)
Description
The current test strategy for carcinogenicity is generally based on in vitro and in vivo genotoxicity assays. Non-genotoxic carcinogens (NGTXC) are negative for genotoxicity and go undetected. Therefore, alternative tests to detect these chemicals are urgently needed. NGTXC act through different modes of action, which complicates the development of such assays. We have demonstrated recently in primary mouse hepatocytes that some, but certainly not all, NGTXC can be categorized according to their mode of action based on feature detection at a gene expression level (Schaap et al. 2012, PMID22710402). Identification of a wider range of chemicals probably requires multiple in vitro systems. In the current study we describe the added value of using mouse embryonic stem cells. In this study the focus is on NGTXC, but we also included genotoxic carcinogens and non-carcinogens. This approach enables us to assess the robustness of this method and to evaluate the system for recognizing features of chemicals in general, which is important for application in future risk assessment.
Publication Title
A novel toxicogenomics-based approach to categorize (non-)genotoxic carcinogens.
Sample Metadata Fields
Specimen part
View Samples
GSE54257- Mus musculus, Homo sapiens
- 116 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302), Affymetrix HT HG-U133+ PM Array Plate (hthgu133pluspm)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNFα-mediated hepatotoxicity.
Sample Metadata Fields
Sex, Age, Specimen part, Cell line, Treatment, Subject
View Samples- Homo sapiens
- 96 Downloadable Samples
Affymetrix HT HG-U133+ PM Array Plate (hthgu133pluspm)
Description
Drug-induced liver injury (DILI) is an important clinical problem. Here we used a genomics approach to establish the critical drug-induced toxicity pathways that act in synergy with the pro-inflammatory cytokine tumor necrosis factor (TNF) to cause cell death of liver HepG2 cells. Transcriptomics of the cell injury stress response pathways initiated by two hepatoxicants, diclofenac and carbamazepine, revealed the endoplasmic reticulum (ER) stress/translational initiation signaling and Nrf2 antioxidant signaling as two major affected pathways, which was similar to that observed for the majority of ~80 DILI compounds in primary human hepatocytes. The ER stress was primarily related to PERK and ATF4 activation and subsequent expression of CHOP, which was all independent of TNF signaling. Identical ATF4 dependent transcriptional programs were observed in primary human hepatocytes as well as primary precision cut human liver slices. Targeted RNA interference studies revealed that while ER stress signaling through IRE1 and ATF6 acted cytoprotective, activation of the ER stress protein kinase PERK and subsequent expression of CHOP was pivotal for the onset of drug/TNF-induced apoptosis. While inhibition of the Nrf2-dependent adaptive oxidative stress response enhanced the drug/TNF cytotoxicity, Nrf2 signaling did not affect CHOP expression. Both hepatotoxic drugs enhanced expression of the translational initiation factor EIF4A1, which was essential for CHOP expression and drug/TNF-mediated cell killing. Our data support a model in which enhanced drug-induced translation initiates PERK-mediated CHOP signaling in an EIF4A1 dependent manner, thereby sensitizing towards caspase-8-dependent TNF induced apoptosis.
Publication Title
Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNFα-mediated hepatotoxicity.
Sample Metadata Fields
Cell line, Treatment
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Drug-induced liver injury (DILI) is an important clinical problem. Here we used a genomics approach to establish the critical drug-induced toxicity pathways that act in synergy with the pro-inflammatory cytokine tumor necrosis factor (TNF) to cause cell death of liver HepG2 cells. Transcriptomics of the cell injury stress response pathways initiated by two hepatoxicants, diclofenac and carbamazepine, revealed the endoplasmic reticulum (ER) stress/translational initiation signaling and Nrf2 antioxidant signaling as two major affected pathways, which was similar to that observed for the majority of ~80 DILI compounds in primary human hepatocytes. The ER stress was primarily related to PERK and ATF4 activation and subsequent expression of CHOP, which was all independent of TNF signaling. Identical ATF4 dependent transcriptional programs were observed in primary human hepatocytes as well as primary precision cut human liver slices. Targeted RNA interference studies revealed that while ER stress signaling through IRE1 and ATF6 acted cytoprotective, activation of the ER stress protein kinase PERK and subsequent expression of CHOP was pivotal for the onset of drug/TNF-induced apoptosis. While inhibition of the Nrf2-dependent adaptive oxidative stress response enhanced the drug/TNF cytotoxicity, Nrf2 signaling did not affect CHOP expression. Both hepatotoxic drugs enhanced expression of the translational initiation factor EIF4A1, which was essential for CHOP expression and drug/TNF-mediated cell killing. Our data support a model in which enhanced drug-induced translation initiates PERK-mediated CHOP signaling in an EIF4A1 dependent manner, thereby sensitizing towards caspase-8-dependent TNF induced apoptosis.
Publication Title
Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNFα-mediated hepatotoxicity.
Sample Metadata Fields
Sex, Age, Specimen part, Treatment
View Samples- Homo sapiens
- 10 Downloadable Samples
- Affymetrix HT HG-U133+ PM Array Plate (hthgu133pluspm)
Description
Drug-induced liver injury (DILI) is an important clinical problem. Here we used a genomics approach to establish the critical drug-induced toxicity pathways that act in synergy with the pro-inflammatory cytokine tumor necrosis factor (TNF) to cause cell death of liver HepG2 cells. Transcriptomics of the cell injury stress response pathways initiated by two hepatoxicants, diclofenac and carbamazepine, revealed the endoplasmic reticulum (ER) stress/translational initiation signaling and Nrf2 antioxidant signaling as two major affected pathways, which was similar to that observed for the majority of ~80 DILI compounds in primary human hepatocytes. The ER stress was primarily related to PERK and ATF4 activation and subsequent expression of CHOP, which was all independent of TNF signaling. Identical ATF4 dependent transcriptional programs were observed in primary human hepatocytes as well as primary precision cut human liver slices. Targeted RNA interference studies revealed that while ER stress signaling through IRE1 and ATF6 acted cytoprotective, activation of the ER stress protein kinase PERK and subsequent expression of CHOP was pivotal for the onset of drug/TNF-induced apoptosis. While inhibition of the Nrf2-dependent adaptive oxidative stress response enhanced the drug/TNF cytotoxicity, Nrf2 signaling did not affect CHOP expression. Both hepatotoxic drugs enhanced expression of the translational initiation factor EIF4A1, which was essential for CHOP expression and drug/TNF-mediated cell killing. Our data support a model in which enhanced drug-induced translation initiates PERK-mediated CHOP signaling in an EIF4A1 dependent manner, thereby sensitizing towards caspase-8-dependent TNF induced apoptosis.
Publication Title
Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNFα-mediated hepatotoxicity.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
Human transcriptome analysis of U2OS cells treated with nocodazole or DMSO (Control).
Publication Title
Autophagy Governs Protumorigenic Effects of Mitotic Slippage-induced Senescence.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 3 Downloadable Samples
NextSeq 500
Description
The NuRD complex is generally thought to repress transcription at both hyper- and hypomethylated regions in the genome. In addition, the complex is involved in the DNA damage response. Here, we show that ZMYND8 bridges NuRD to a number of putative DNA-binding zinc finger proteins. The ZMYND8 MYND domain directly interacts with PPPL? motifs in the NuRD subunit GATAD2A. Furthermore, GATAD2A and GATAD2B exclusively form homodimers and they thus define mutually exclusive NuRD subcomplexes. ZMYND8 and MBD3 share a large number of genome-wide binding sites, mostly active promoters and enhancers. Depletion of ZMYND8 does not affect NuRD occupancy genome-wide and expression of NuRD/ZMYND8 target genes in steady-state asynchronous cells. However, ZMYND8 facilitates immediate recruitment of GATAD2A/NuRD to induced sites of DNA damage. These results thus show that a specific substoichiometric interaction with a NuRD subunit paralogue provides unique functionality to a distinct NuRD subcomplex. Overall design: RNA-seq samples for HeLa FRT-TO mock, ZMYND8KO, and ZMYND8KO-rescue cells
Publication Title
ZMYND8 Co-localizes with NuRD on Target Genes and Regulates Poly(ADP-Ribose)-Dependent Recruitment of GATAD2A/NuRD to Sites of DNA Damage.
Sample Metadata Fields
Subject
View Samples- Sus scrofa
- 24 Downloadable Samples
- Porcine Gene 1.1 ST Array (porgene11st)
Description
An early settlement of a complex gut microbiota can protect against gastro-intestinal dysbiosis, but the effects of neonatal microbiota colonization and early life feeding of medium chain triglycerides on the maturation of the porcine gastric mucosa are largely unknown.
Publication Title
The effects of starter microbiota and the early life feeding of medium chain triglycerides on the gastric transcriptome profile of 2- or 3-week-old cesarean delivered piglets.
Sample Metadata Fields
Specimen part
View Samples- Sus scrofa
- 12 Downloadable Samples
- Porcine Gene 1.1 ST Array (porgene11st)
Description
An early settlement of a complex gut microbiota can protect against gastro-intestinal dysbiosis, but the effects of neonatal microbiota colonization on the maturation of the porcine gastric mucosa are largely unknown.
Publication Title
The effects of starter microbiota and the early life feeding of medium chain triglycerides on the gastric transcriptome profile of 2- or 3-week-old cesarean delivered piglets.
Sample Metadata Fields
Specimen part
View Samples- Arabidopsis thaliana
- 18 Downloadable Samples
- Affymetrix Arabidopsis ATH1 Genome Array (ath1121501)
Description
Arabidopsis plants were treated either with mock or MSB (0.2 mM of Menadione sodium bisulphite). <br></br>Tissue was sampled after 3, 6 and 24 hours.
Publication Title
Molecular analysis of menadione-induced resistance against biotic stress in Arabidopsis.
Sample Metadata Fields
Age, Specimen part, Compound, Time
View Samples