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SRP001450
Caenorhabditis elegans
3 Downloadable Samples
Illumina Genome Analyzer II
Description
High-throughput pyrosequencing of endogenous small RNAs from CSR-1 IP complexes and csr-1(tm892) and ego-1(om97) mutants with corresponding controls. RNAi-related pathways regulate diverse processes, from developmental timing to transposon silencing. Here, we show that in C. elegans the Argonaute CSR-1, the RNA-dependent RNA polymerase EGO-1, the Dicer-related helicase DRH-3, and the Tudor-domain protein EKL-1 localize to chromosomes and are required for proper chromosome segregation. In the absence of these factors chromosomes fail to align at the metaphase plate and kinetochores do not orient to opposing spindle poles. Surprisingly, the CSR-1 interacting small RNAs (22G-RNAs) are antisense to thousands of germline-expressed protein-coding genes. Nematodes assemble holocentric chromosomes in which continuous kinetochores must span the expressed domains of the genome. We show that CSR-1 interacts with chromatin at target loci, but does not down-regulate target mRNA or protein levels. Instead, our findings support a model in which CSR-1 complexes target protein-coding domains to promote their proper organization within the holocentric chromosomes of C. elegans. Overall design: 5 samples examined. Small RNAs that co-immunopercipitate with CSR-1 protein and input sample. Small RNAs from csr-1(tm892) and ego-1(om97) mutants and corresponding congenic wild type strain.
Publication Title
The Argonaute CSR-1 and its 22G-RNA cofactors are required for holocentric chromosome segregation.
Sample Metadata Fields
Cell line, Subject
View Samples- Mus musculus
- 32 Downloadable Samples
Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
The cholecystokinin B (2) receptor knockout (Cckbr KO) protects against allodynia induced by chronic constriction injury (CCI). The mechanism of this phenomenon is unknown, but must involve persistent changes in pain modulation and/or inflammatory pathways. We performed a gene expression study in two brain areas (midbrain and medulla) after surgical induction of CCI in Cckbr KO and wild-type (wt) control mice. The patterns of gene expression differences suggest that the immune system is activated in higher brain structures following CCI in the wt mice. The strongest differences include genes related to the MAPK pathway activation and cytokine production. In Cckbr KO mice this expressional pattern was absent. In addition, we found significant elevation of the Toll-like receptor 4 (Tlr4) in the supraspinal structures of the mice with deleted Cckbr compared to wt control mice. This up-regulation is most likely induced by the deletion of Cckbr. We suggest that there is a functional deficiency in the Tlr4 pathway which disables the development of neuropathic pain in Cckbr KO mice. Indeed, real time PCR analysis detected a CCI-induced upregulation of Tlr4 and Il1b expression in the lumbar region of wt but not Cckbr KO mice. Gene expression profiling indicates that elements of the immune response are not activated in Cckbr KO mice following CCI. Our findings suggest that there may be a role for CCK in the regulation of innate immunity.
Publication Title
Gene expression profiling reveals upregulation of Tlr4 receptors in Cckb receptor deficient mice.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 120 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
Analysis of livers of male and female B6C3F1 mice exposed to prototype treatments from five classes of model hepatotoxicants. These hepatotoxicants include compounds that activate the peroxisome proliferator-activated receptor (PPAR), induce the inflammatory response, activate the constitutive androstane receptor (CAR), stimulate the hypoxia signal transduction pathway, and activate the aryl-hydrocarbon receptor (AHR). The results provide insights into the shared and unique pathways that are activated across these model hepatotoxicants.
Publication Title
Screening a mouse liver gene expression compendium identifies modulators of the aryl hydrocarbon receptor (AhR).
Sample Metadata Fields
Sex, Age, Compound, Time
View Samples- Mus musculus
- 47 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
PPAR-null and wild-type male mice treated with PFHxS or PFNA
Publication Title
Screening a mouse liver gene expression compendium identifies modulators of the aryl hydrocarbon receptor (AhR).
Sample Metadata Fields
Sex, Specimen part, Compound
View Samples- Mus musculus
- 16 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Many environmentally-relevant chemicals and drugs activate the nuclear receptor pregnane X receptor (PXR). Activation of PXR can lead to increases in liver weight in part through hepatocyte replication similar to a large number of compounds that activate other nuclear receptors such as the peroxisome proliferator-activated receptor alpha and the constitutive activated receptor (CAR). PXR controls the expression of a large battery of genes involved in xenobiotic metabolism. Identification of genes that are accurate predictors of PXR activation would be useful in high-throughput screens to assess potential toxicity and drug-drug interactions. Here, we identified PXR-dependent genes in the mouse liver after exposure to pregnenolone 16alpha-carbinonitrile (PCN), a chemical that is often used as a model PXR agonist.
Publication Title
Screening a mouse liver gene expression compendium identifies modulators of the aryl hydrocarbon receptor (AhR).
Sample Metadata Fields
Sex, Specimen part, Compound
View Samples- Mus musculus
- 13 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Therapeutic hypothermia is a clinically effective treatment for various hypoxic and ischemic conditions, but the associated molecular mechanisms remain unclear. To gain insight into hypothermia-induced transcriptional response, mouse embryonic fibroblasts were exposed to mild hypothermia (32C) or normothermia (37C) for increasing time periods. We aimed to identify genes with temporally near-monotonic response as the most obvious candidates for mediating the therapeutic effects of hypothermia.
Publication Title
Estimating differential expression from multiple indicators.
Sample Metadata Fields
Specimen part, Time
View Samples- Mus musculus
- 3 Downloadable Samples
- Illumina HiSeq 2000
Description
To study the role of epigenetics and hormones on hematopoietic stem cell function, hematopoietic stem and progenitor (LSK) cells were sorted from E14.5 embryos of wild-type, DNMT3B7 hemizygous or DNMT3B7 homozygous genotype. The expression analysis was performed to provide information regarding the mechanism by which hormones regulate hematopoiesis. Overall design: Hematopoietic stem and progenitor (LSK) cells from E14.5 murine embryonic fetal livers of wild-type, or DNMT3B7 transgenic genotypes were flow-sorted, and RNA isolated for expression analysis by RNA-Sequencing
Publication Title
Epigenetic Control of Apolipoprotein E Expression Mediates Gender-Specific Hematopoietic Regulation.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
WFS1 gene is coding protein with unknown function but its functional deficiency causes different neuropsychiatric and neuroendocrine syndromes. In the present study we aimed to find the functional networks influenced by the Wfs1 deficiency in the hypothalamus. We performed gene expression profiling (Mouse Gene 1.0 ST Arrays) in Wfs1 deficient mice (ko). Modified t-statistics was used for comparison of groups (wt vs ko). Functional annotation of the alterations in RNA levels was performed with Ingenuity Pathway Analysis. 305 genes were differentially expressed with nominal p-value less than 0.01. FDR adjusted p-values were significant (0.007) only for two genes C4b (t=9.66) and Wfs1 (t=-9.03). However, several genes related to the G-protein signalling were very close to the FDR adjusted significance. For instance, Rgs4 (regulator of G-protein signalling 4) was down-regulated (-0.34, t=-5.4) in Wfs1 deficient mice. Changes in Rgs4 and C4B expression were confirmed by QRT-PCR. In humans, Rgs4 is in the locus for bipolar disease (BPD) and its expression is down-regulated in BPD. C4b is the gene related to the neurodegenerative diseases. In conclusion, hypothalamic gene expression profiling indicates alterations in some functionally relevant molecular pathways explaining the clinical syndrome in the Wolfram syndrome patients.
Publication Title
Hypothalamic gene expression profile indicates a reduction in G protein signaling in the Wfs1 mutant mice.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 35 Downloadable Samples
- Illumina HiSeq 2500
Description
Retinopathy of prematurity (ROP) is the most common cause of childhood blindness worldwide and is caused by oxygen therapy necessary to prevent mortality after premature birth. We have previously demonstrated the efficacy of systemic hypoxia inducible factor (HIF) stabilization through HIF prolyl hydroxylase inhibition (HIF PHi) in protecting retinal vasculature from oxygen toxicity in a mouse model of ROP or oxygen induced retinopathy (OIR). We definitively demonstrated that hepatic HIF-1 can be activated to confer this protection using systemic dimethyloxalylglycine (DMOG) to prevent HIF-1a degradation. In this study we compare Roxadustat, a small molecule stabilizer of HIF-1 currently in phase 3 clinical trials for increasing erythropoiesis in adult patients with chronic kidney disease, to DMOG. We demonstrate that Roxadustat induces vascular protection during hyperoxia to induce the coordinated sequential growth of retinal vasculature with a 3-fold reduction in oxygen induced capillary loss (p-=0.001). In order to define the molecular mechanism of protection, we further compared the transcriptome of both liver and retina after systemic treatment with Roxadustat or DMOG. Similar gene expression profiles were identified in liver but very different effects on transcription were found in retinal tissues because Roxadustat, in contrast to DMOG, directly targets retina, confirmed by western blot and by rescue of the hepatic HIF-1 KO, two criteria that DMOG treatment is unable to fulfill. Systems pharmacologic analysis demonstrates that Roxadustat induces typical HIF regulated genes critical to aerobic glycolysis in liver and retinal tissues whereas DMOG, acting through either secreted hepatokines or by influence of systemic DMOG, downregulates cell adhesion/extracellular matrix interaction pathways while increasing expression of histone cluster genes. Stratification of liver transcriptomes to secreted gene products again shows close consensus of hepatic genes induced by both small molecules, and includes upregulation of a plethora of angiogenic proteins such as plasminogen activator inhibitor (PAI-1), erythropoietin (EPO), and orosomucosoid 2 (ORM2). Secondary validation of these transcripts by serum ELISA confirms secretion of EPO and PAI-1 into blood from liver. These findings definitively demonstrate that HIF stabilization can prevent OIR by two pathways: direct retinal HIF stabilization and induction of aerobic glycolysis or indirect, hepatic HIF-1 stabilization and increased serum angiokines. Systems pharmacology analysis therefore explains why intermittent, low dosage of small molecule HIF stabilizers creates a profound protective phenotype, because both pathways can take advantage of cytoprotection induced by the liver and by retina synergistically. These data provide a rationale for considering low dose, intermittent systemic administration of Roxadustat, currently in phase 3 trials in adults with chronic kidney disease, to eradicate ROP in children. Overall design: RNA-Seq of mice treated with PBS (control), DMOG, or Roxadustat from liver or retina.
Publication Title
Comparative systems pharmacology of HIF stabilization in the prevention of retinopathy of prematurity.
Sample Metadata Fields
Specimen part, Cell line, Treatment, Subject
View Samples- Mus musculus
- 48 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Aim of the present study was to compare the effect of chronic VPA treatment in wild type and Wfs1 knockout mice on hepatic gene expression profile.
Publication Title
Effect of chronic valproic Acid treatment on hepatic gene expression profile in wfs1 knockout mouse.
Sample Metadata Fields
Sex, Specimen part
View Samples