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GSE13590
Mus musculus
12 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
MicroRNAs (miRNAs) are short noncoding RNA molecules regulating the expression of mRNAs. Target identification of miRNAs is computationally difficult due to the relatively low homology between miRNAs and their targets. We present here an experimental approach to target identification where the cartilage-specific miR-140 was overexpressed and silenced in cells it is normally expressed in separate experiments. Expression of mRNAs was profiled in both experiments and the intersection of mRNAs repressed by miR-140 overexpression and derepressed by silencing of miR-140 was identified. The intersection contained only 49 genes, although both treatments affected the accumulation of hundreds of mRNAs. These 49 genes showed a very strong enrichment for the miR-140 seed sequence implying that the approach is efficient and specific. 21 of these 49 genes were predicted to be direct targets based on the presence of the seed sequence. Interestingly, none of these were predicted by the published target prediction methods we used. One of the potential target mRNAs, Cxcl12, was experimentally validated by Northern blot analysis and a luciferase reporter assay.
Publication Title
Experimental identification of microRNA-140 targets by silencing and overexpressing miR-140.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 2 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
DNA damage plays a major role in neural cell death by necrosis and/or apoptosis. However, our understanding of the molecular mechanisms of neural cell death remains still incomplete. To acquire a global understanding of the various mediators related to DNA damage-induced neural cell death pathways, we performed a whole genomic wide screen in neural stem cells by using a siRNA library. We identified 80 genes required for DNA damage-induced cell death. 14 genes (17.5%) are directly related to cell death and/or apoptosis. 66 genes have not been previously directly linked to DNA damage-induced cell death. Using an integrated approach with functional and bioinformatics analysis, we have uncovered a molecular network containing several partially overlapping and interconnected pathways and/or protein complexes that are required for DNA damage-induced neural cell death. The identification of the network of neural cell death mediators will greatly enhance our understanding of the molecular mechanisms of neural cell death and provide therapeutic targets for nervous system disorders.
Publication Title
High-Content Genome-Wide RNAi Screen Reveals <i>CCR3</i> as a Key Mediator of Neuronal Cell Death.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 189 Downloadable Samples
Description
Estrogen receptor positive (ER+) breast cancers that develop resistance to therapies that target the ER are the most common cause of breast cancer death. Beyond mutations in ER, which occur in 25-30% of patients treated with aromatase inhibitors (AIs), our understanding of clinical mechanisms of resistance to ER-directed therapies remains incomplete. We identified activating HER2 mutations in metastatic biopsies from eight patients with ER+ metastatic breast cancer who had developed resistance to ER-directed agents, including AIs, tamoxifen, and fulvestrant. Examination of treatment-naïve primary tumors in five patients revealed no evidence of pre-existing mutations in four of five patients, suggesting that these mutations were acquired under the selective pressure of ER-directed therapy. These mutations were mutually exclusive with ER mutations, suggesting a distinct mechanism of acquired resistance to ER-directed therapies. In vitro analysis confirmed that these mutations conferred estrogen independence. In addition, and in contrast to ER mutations, these mutations resulted in resistance to tamoxifen, fulvestrant, and the CDK4/6 inhibitor palbociclib. Resistance was overcome by combining ER-directed therapy with the irreversible HER2 kinase inhibitor neratinib, highlighting an effective treatment strategy in these patients. Overall design: Examination of the transcriptional output (mRNA) of the HER2 activating mutations compared with controls under various drugs. Specifically, we expressed the activating mutations S653C, L755S, V777L, and L869R in ER+/HER2- breast cancer cell line (T47D), and controls (GFP, wild-type HER2, kinase-dead HER2, and ESR1 Y537S). Cell were then treated with DMSO, 1µM fulvestrant, 1µM neratinib, 10µM palbociclib, 1µM fulvestrant + 1µM neratinib, or 1µM fulvestrant + 10µM palbociclib for 24 hours. All experimental conditions were done in 6 replicates, sequenced in 3 replicates
Publication Title
Acquired HER2 mutations in ER<sup>+</sup> metastatic breast cancer confer resistance to estrogen receptor-directed therapies.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 2 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The discovery of mammalian cardiac progenitor cells has suggested that the heart consists of not only terminally differentiated beating cardiomyocytes, but also a population of self-renewing stem cells with the potential to generate new cardiomyocytes (Anderson, Self et al. 2007; Bearzi, Rota et al. 2007; Wu, Chien et al. 2008). A consequence of longevity is continual exposure to environmental and xenobiotic stresses, and recent literature suggests that hematopoietic stem cell pools tightly control cell health through upregulation of the integrated stress response and consequent cellular mechanisms such as apoptosis. However, whether or not this biological response is conserved in progenitor cells for later lineages of tissue specific stem cells is not well understood. Using human induced pluripotent stem cells (iPSC) of both cardiac progenitor and mature cardiomyocyte lineages, we found that the integrated stress response was upregulated in the iPSC cardiac progenitors leading to an increased sensitivity for apoptosis relative to the mature cardiomyocytes. Of interest, C/EBP homologous protein (CHOP) signaling plays a mechanistic role in the cell death phenotype observed in iPSC progenitors, by which depletion of CHOP prevents cell death following cellular stress by thapsigargin exposure. Our studies suggest that the integrated stress response plays a unique role in maintaining iPSC cardiac progenitor cellular integrity by removing unhealthy cells via apoptosis following environmental and xenobiotic stresses, thus preventing differentiation and self-renewal of damaged cells.
Publication Title
The Integrated Stress Response Regulates Cell Health of Cardiac Progenitors.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Mus musculus
- 5 Downloadable Samples
- Illumina Genome Analyzer IIx
Description
Regeneration of lung epithelium is vital for maintaining airway function and integrity. An imbalance between epithelial damage and repair is at the basis of numerous chronic lung diseases such as asthma, COPD, pulmonary fibrosis and lung cancer. IGF (Insulin-like Growth Factors) signaling has been associated with most of these respiratory pathologies, although their mechanisms of action in this tissue remain poorly understood. Expression profiles analyses of IGF system genes performed in mouse lung support their functional implication in pulmonary ontogeny. Immuno-localization revealed high expression levels of Igf1r (Insulin-like Growth Factor 1 Receptor) in lung epithelial cells, alveolar macrophages and smooth muscle. To further understand the role of Igf1r in pulmonary homeostasis, two distinct lung epithelial-specific Igf1r mutant mice were generated and studied. The lack of Igf1r disturbed airway epithelial differentiation in adult mice revealed enhanced proliferation and altered morphology in distal airway club cells. During recovery after naphthalene-induced club cell injury, the kinetics of terminal bronchiolar epithelium regeneration was hindered in Igf1r mutants, revealing increased proliferation and delayed differentiation of club and ciliated cells. Amid airway restoration, lungs of Igf1r deficient mice showed increased levels of Igf1, Insr, Igfbp3 and epithelial precursor markers, reduced amounts of Scgb1a1 protein, and alterations in IGF signaling mediators. These results support the role of Igf1r in controlling the kinetics of cell proliferation and differentiation during pulmonary airway epithelial regeneration after injury. Overall design: Lung mRNA profiles of 3 months-old Igf1rfl/fl normal/control transgenic mice were generated by deep sequencing using Illumina GAIIx. ------------------------------------------- Submitter states "we use data on the absolute transcription levels (FPKM) of same IGF system genes on the adult "normal" mouse lung to compare them with those reported in the human adult lung (expressed in both as FPKM) (http://www.proteinatlas.org/)".
Publication Title
Involvement of Igf1r in Bronchiolar Epithelial Regeneration: Role during Repair Kinetics after Selective Club Cell Ablation.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
Insight into the role of Insulin-like Growth Factor (IGF) in development of lungs has come from the study of genetically modified mice. IGF1 is a key factor during lung development. IGF1 deficiency in the neonatal mouse causes respiratory failure collapsed alveoli and altered alveolar septa. To further characterize IGF1 function during lung development we analyzed Igf1-/- mouse prenatal lungs in a C57Bl/6 genetic background. Mutant lungs showed disproportional hypoplasia, disorganized extracellular matrix and dilated alveolar capillaries. IGF1 target genes during lung maturation were identified by analyzing RNA differential expression in Igf1-/- lungs using microarrays.
Publication Title
Transcriptome analysis in prenatal IGF1-deficient mice identifies molecular pathways and target genes involved in distal lung differentiation.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 5 Downloadable Samples
- IlluminaGenomeAnalyzerIIx
Description
Comparison of expression profile of Ewing''s sarcoma with cell of origin, mesenchymal stem cells with the goal of identifying novel therapeutic targets. Overall design: 3 Ewing''s cell lines compared to 2 MSC cell lines
Publication Title
Exploring the surfaceome of Ewing sarcoma identifies a new and unique therapeutic target.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 49 Downloadable Samples
- Illumina HiSeq 2000
Description
To determine whether an accelerated aging-like phenotype occurs in hematopoiesis of young Tif1?-/- mice (4 months old), we purified 200,000 hematopoietic stem cells (LSK: Lineage negative, Sca1+, c-Kit+) from Tif1?-/- mice and performed high-throughput mRNA sequencing (RNA-seq). We compared this transcriptome to physiological aging by creating two other RNAseq libraries from young (4 months old) and old (20 months old) wild type mice. Overall design: RNAseq study on young Tif1?-/- mice (4 months old), young wild type mice (4 months old) and old wild type mice (20 months old).
Publication Title
Tif1γ regulates the TGF-β1 receptor and promotes physiological aging of hematopoietic stem cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 48 Downloadable Samples
- NextSeq 500
Description
We report that the HF/HS-mediated functional enrichment of genes of immunity and inflammation is driven toward normal by the AOF supplementation Obesity may not constantly associate with metabolic disorders and mortality later in life, raising the challenging concept of healthy obesity. Here, high fat-high sucrose (HF/HS) feeding produces hyperglycaemia and hypercholesterolemia, increases oxidative stress, elevates endotoxemia, expands adipose tissue (with enlarged adipocytes, macrophage infiltration and accumulation of cholesterol and oxysterols), and reduces lifespan of obese mice. Despite persistence of obesity, supplementation with an antioxidant formulation normalizes plasma lipids and endotoxemia, prevents macrophage recruitment in adipose tissue, reduces adipose accumulation of cholesterol and cholesterol oxides, and extends lifespan. The HF/HS-mediated functional enrichment of genes of immunity and inflammation (in particular response to lipopolysaccharides) is driven towards normal by the antioxidant formulation. It is concluded that the limitation of immune cell infiltration in adipose tissue on the long term by an antioxidant formulation can increase lifespan independently of body weight and fat storage. It constitutes the hallmark of a healthy adiposity trait. Overall design: Examination of the expression profile of mice adipose tissues fed either standard (Std), High-fat/high-sucrose (HF/HS) or HF/HS + antioxidant formulation (AOF) for 180 days
Publication Title
Healthy adiposity and extended lifespan in obese mice fed a diet supplemented with a polyphenol-rich plant extract.
Sample Metadata Fields
Age, Specimen part, Cell line, Subject
View Samples- Mus musculus
- 144 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
High-fat diets are associated with increased obesity and metabolic disease in mice and humans. Here we used analysis of variance (ANOVA) to scrutinize a microarray data set consisting of 10 inbred strains of mice from both sexes fed atherogenic high-fat and control chow diets. An overall F-test was applied to the 40 unique groups of strain-diet-sex to identify 15,288 genes with altered transcription. Bootstrapping k-means clustering separated these changes into four strain-dependent expression patterns, including two sex-related profiles and two diet-related profiles. Sex-induced effects correspond to secretion (males) or fat and energy metabolism (females), whereas diet-induced changes relate to neurological processes (chow) or immune response (high-fat). The full set of pairwise contrasts for differences between strains within sex (90 different statistical tests) uncovered 32,379 total changes. These differences were unevenly distributed across strains and between sexes, indicating that strain-specific responses to high-fat diet differ between sexes. Correlations between expression levels and 8 obesity-related traits identified 5,274 associations between transcript abundance and measured phenotypic endpoints. From this number, 2,678 genes are positively correlated with total cholesterol levels and associate with immune-related categories while 2,596 genes are negatively correlated with cholesterol and connect to cholesterol synthesis.
Publication Title
Practical applications of the bioinformatics toolbox for narrowing quantitative trait loci.
Sample Metadata Fields
Sex
View Samples