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SRP100979
Mus musculus
24 Downloadable Samples
Illumina HiSeq 2000
Description
The heat shock response (HSR) is a mechanism to cope with proteotoxic stress by inducing the expression of molecular chaperones and other heat shock response genes. The HSR is evolutionarily well conserved and has been widely studied in bacteria, cell lines and lower eukaryotic model organisms. However, mechanistic insights into the HSR in higher eukaryotes, in particular in mammals, are limited. We have developed an in vivo heat shock protocol to analyze the HSR in mice and dissected heat shock factor 1 (HSF1)-dependent and -independent pathways. Whilst the induction of proteostasis-related genes was dependent on HSF1, the regulation of circadian function related genes, indicating that the circadian clock oscillators have been reset, was independent of its presence. Furthermore, we demonstrate that the in vivo HSR is impaired in mouse models of Huntington's disease but we were unable to corroborate the general repression of transcription after a heat shock found in lower eukaryotes. Overall design: RNA-Seq was performed on mRNA isolated from quadriceps femoris muscle of 24 mice. These mice were of wild type, R6/2, and Hsf1-/- genotypes. Two mice of each genotype were tested in four conditions: (1) heat shock, (2) control heat shock, (3) HSP90 inhibition (NVP-HSP990), and (4) HSP90 inhibition vehicle.
Publication Title
HSF1-dependent and -independent regulation of the mammalian in vivo heat shock response and its impairment in Huntington's disease mouse models.
Sample Metadata Fields
Age, Specimen part, Treatment, Subject
View Samples- Mus musculus
- 14 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Disruption of local iron homeostasis is a common feature of neurodegenerative diseases. We focused on dopaminergic neurons, asking how iron transport proteins modulate iron homeostasis in vivo. Inactivation of the transmembrane iron exporter ferroportin had no apparent consequences. However, loss of the transferrin receptor 1, involved in iron uptake, caused profound, age-progressive neurodegeneration with features similar to Parkinsons disease. There was gradual loss of dopaminergic projections in the striatum with subsequent death of dopaminergic neurons in the substantia nigra. After depletion of 30% of the neurons the mice developed neurobehavioral parkinsonism, with evidence of mitochondrial dysfunction and impaired mitochondrial autophagy. Molecular analysis revealed strong signatures indicative of attempted axonal regeneration, a metabolic switch to glycolysis and the unfolded protein response. We speculate that cellular iron deficiency may contribute to neurodegeneration in human patients
Publication Title
Altered dopamine metabolism and increased vulnerability to MPTP in mice with partial deficiency of mitochondrial complex I in dopamine neurons.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 26 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Huntingtons disease (HD) is a neurodegenerative disorder that is associated with the deposition of proteinaceous aggregates in the brains of HD patients and mouse models. Previous studies have suggested that wide-scale disruption of protein homeostasis occurs in protein folding diseases. Protein homeostasis can be maintained by activation of the heat shock response (HSR) via the transcription factor heat shock factor 1 (HSF1), the pharmacological activation of which can be achieved by Hsp90 inhibition and has been demonstrated to be beneficial in cell and invertebrate models of HD. Whether the HSR is functional in HD and whether its activation has therapeutic potential in mammalian HD models is currently unknown. To address these issues, we used a novel, brain penetrant Hsp90 inhibitor to activate the HSR in brain after systemic administration. Microarrays, quantitative PCR and western blotting showed that the HSR becomes impaired with disease progression in two mouse models of HD and that this originates at the level of transcription.
Publication Title
Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease.
Sample Metadata Fields
Sex, Age, Specimen part, Treatment
View Samples- Homo sapiens
- 22 Downloadable Samples
- Illumina HiSeq 2500, NextSeq 550
Description
Transcriptional cofactors communicate regulatory cues from enhancers to promoters and are central effectors of transcription activation and gene expression, which is a hallmark of all multicellular organisms. However, the extent to which different cofactors display intrinsic specificity for distinct promoters is unclear. Testing intrinsic COF – core promoter (CP) compatibilities requires the systematic assessment of transcriptional activation for many CPs in the presence or absence of a given COF in an otherwise constant standardized reporter system. We therefore combined a plasmid-based high-throughput reporter assay, Self-Transcribing Active Core Promoter-sequencing (STAP-seq), with the specific recruitment of individual COFs to create a high-throughput activator bypass-like assay. Using this assay, we tested whether 5 different individually tethered human COFs (MED15, BRD4, EP300, MLL3 and EMSY) activate transcription from a selection of 12,000 candidate sequences encompassing different types of gene core promoters, enhancers and control sequences. In addition, we used the strong transcriptional activator P65 as a positive control and GFP as a negative control. We found that different COFs preferentially activate different CPs. For instance, MED15 prefers TATA-box containing CPs, while MLL3 preferentially activates CpG island promoters. The observed compatibilities between cofactors and promoters can explain how different enhancers specifically activate distinct sets of genes or alternative promoters within the same gene, and may underlie distinct transcriptional programs in human cells. Overall design: STAP-seq upon recruitment of individual transcriptional cofactor in HCT116 cells with 5 different cofactors and 2 controls, each in biological triplicate.
Publication Title
Transcriptional cofactors display specificity for distinct types of core promoters.
Sample Metadata Fields
No sample metadata fields
View Samples- Arabidopsis thaliana
- 7 Downloadable Samples
- Affymetrix Arabidopsis ATH1 Genome Array (ath1121501)
Description
Cadmium sulfide quantum dots (CdS QDs) are widely used in novel equipment. The relevance of the research lies in the need to develop risk assessments for nanomaterials, using as basis a model plant species.
Publication Title
Genome-wide approach in Arabidopsis thaliana to assess the toxicity of cadmium sulfide quantum dots.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Caenorhabditis elegans
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
We performed RNA-seq analysis of WT and blmp-1(tm548) mutant L3 larvae to identify genes regulated by the zing-finger transcription factor BLMP-1. Overall design: We analyzed three WT and three blmp-1 mutant biological replicates
Publication Title
DRE-1/FBXO11-dependent degradation of BLMP-1/BLIMP-1 governs C. elegans developmental timing and maturation.
Sample Metadata Fields
Cell line, Subject
View Samples- Homo sapiens
- 10 Downloadable Samples
- Affymetrix Human Genome U133B Array (hgu133b), Affymetrix Human Genome U133A Array (hgu133a)
Description
E47 is a basic Helix Loop Helix (bHLH) transcription factor that has important roles in cell fate determination and differentiation of many cell types. In the nervous system E47 heterodimerizes with tissue-specific, pro-neural bHLH transcription factors and activates downstream target genes. To identify the relevant target genes of bHLH transcription factors in neural cells, we performed gene expression profiling of the human neuroblastoma cell line SK-N-SH engineered to acutely express ectopic E47 by an adenoviral vector. The experiments were done at two time points following adenoviral infection, 8 hours and 20 hours. Genes induced by E47 after 8 hours are likely to be direct targets of this transcription factor.
Publication Title
Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth.
Sample Metadata Fields
Specimen part, Cell line, Time
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
Mouse ES cells were stably transduced with a lentivirus expressing either wild-type KBP or the stable mutant KBP(KK/RR) and maintained in self-renewing growth conditions. RNA-seq was performed to assess mRNA expression differences caused by the stabilization of KBP. Overall design: 6 samples [a triplicate set for ES cells expressing wild-type KBP and a triplicate set expressing KBP(KK/RR)] were analyzed.
Publication Title
The TDH-GCN5L1-Fbxo15-KBP axis limits mitochondrial biogenesis in mouse embryonic stem cells.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 32 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Gene expression analysis of three sets of patient-derived T-ALL xenografted murine lines treated or not treated with Givinostat, to investigate the immediate anti-leukemic effects after 6 hours of in vivo treatment with this histone deacetylase inhibitor.
Publication Title
An immediate transcriptional signature associated with response to the histone deacetylase inhibitor Givinostat in T acute lymphoblastic leukemia xenografts.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina MouseWG-6 v2.0 expression beadchip
Description
Tmprss6 is the master inhibitor of hepcidin and its inactivation causes iron refractory iron deficiency anemia both in human and in mice. Mice with iron deficiency anemia (IDA)-low hepcidin show a pro-inflammatory response that is blunted in iron deficienct-high hepcidin Tmprss6 null mice. We investigated the transcriptional response associated with chronic hepcidin overexpression by comparing whole genome transcription profiling of the liver of Tmprss6 KO mice and IDA animals, irrespective of iron deficiency.
Publication Title
A strong anti-inflammatory signature revealed by liver transcription profiling of Tmprss6-/- mice.
Sample Metadata Fields
Age, Specimen part
View Samples