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GSE57380
Mus musculus
18 Downloadable Samples
Affymetrix Mouse Gene 2.1 ST Array (mogene21st)
Description
Ovarian clear cell carcinoma (OCCC) is an aggressive form of ovarian cancer with high ARID1A mutation rates. Here we present a genetically engineered mouse model of OCCC. We find that ARID1A inactivation is not sufficient for tumor formation, but requires concurrent activation of the phosphoinositide 3-kinase catalytic subunit, PIK3CA. Remarkably, the mice develop highly penetrant tumors with OCCC-like histopathology, culminating in hemorrhagic ascites and a median survival period of 7.5 weeks. Therapeutic treatment with the pan-PI3K inhibitor, BKM120, prolonged mouse survival by inhibiting tumor cell growth. Cross-species gene expression comparisons support a role for IL-6 inflammatory cytokine signaling in OCCC pathogenesis. We further show that ARID1A-PIK3CA mutations cooperate to promote tumor growth through sustained IL-6 overproduction. Our findings establish an epistatic relationship between SWI/SNF chromatin remodeling and PI3K pathway mutations in OCCC and demonstrate that these pathways converge on pro-tumorigenic cytokine signaling. We propose that ARID1A protects against inflammation-driven tumorigenesis.
Publication Title
Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 34 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
The goal of this study was to identify the transcriptional mechanisms involved in the activation of the immune system by QS-21, a triterpene glycoside purified from the bark of Quillaja saponaria which has adjuvant activity in vivo. Saponins represent a promising class of vaccine adjuvant. Together with the TLR4-ligand MPL, QS-21 is part of the Adjuvant System AS01, a key component of the Malaria and Zoster candidate vaccines that display demonstrated clinical efficacy. However, the mechanism of action of QS-21 in this liposomal formulation is poorly understood. Upon intra-muscular immunisation, we observed that QS-21 rapidly accumulated in CD169+ resident macrophages of the draining lymph node where it elicited a local innate immune response. Depletion of these cells abrogated QS-21-mediated innate cell recruitment to the lymph node, dendritic cell (DC) phenotypic maturation as well as the adjuvant effect on T cell and antibody responses to co-administered antigens. DCs rather than lymph node-resident macrophages were directly involved in T cell priming by QS-21 as revealed by the decrease in antigen-specific T cell response in Batf3/ mice. Further analysis showed that the adjuvant effect of QS-21 depended on the integration of Caspase-1 and MyD88 pathways, at least in part through the local release of HMGB1. Taken together, this work unravels the key role of lymph node sentinel macrophage in controlling the adjuvant effect of a molecule proven to improve vaccine response in humans
Publication Title
Central Role of CD169<sup>+</sup> Lymph Node Resident Macrophages in the Adjuvanticity of the QS-21 Component of AS01.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 26 Downloadable Samples
NextSeq 500
Description
Three different progenitor cell subsets in subcutaneous and visceral adipose tissues derived from 5 obese patients were subjected to AmpliSeq transcriptome profiling. Transcriptomic profiles were analyzed to compare progenitor cell subsets and the impact of subcutaneous and visceral adipose tissue location. Overall design: Transcriptomic profiling of 3 different progenitor cell types in subcutaneous and visceral adipose tissues derived from 5 obese patients (3X2X5=30 samples).
Publication Title
Lobular architecture of human adipose tissue defines the niche and fate of progenitor cells.
Sample Metadata Fields
Subject
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
We compared the heart of 6-weeks-old mice (young) with 18-months-old mice (old)
Publication Title
MicroRNA-34a regulates cardiac ageing and function.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 384 Downloadable Samples
- Affymetrix Mouse Gene 1.1 ST Array (mogene11st)
Description
We create catalogues of genes showing significant strain, parent-of-origin, dominance, sex effect in inbreds and reciprocal F1 hybrids of three wild-derived strains (CAST, PWK, WSB) across 4 different tissues (brain, kidney, liver, and lung)
Publication Title
Analyses of allele-specific gene expression in highly divergent mouse crosses identifies pervasive allelic imbalance.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 157 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
The Collaborative Cross (CC) recombinant inbred panel was conceived as an ideal resource for mammalian system genetics. The pre-CC is a proof-of-concept experiment involving CC lines that have undergone at least five generations of inbreeding. Siblings from these lines were each involved in one of four distinct phenotyping arms, then genotyped on a high-density Affymetrix platform. The genetic profile of these emerging lines reveals high diversity, balanced allele frequencies, and well-distributed recombination all ideal qualities for a mapping panel. We have mapped white spot, a discrete trait; body weight, a highly polygenic complex trait; and more than 11,000 liver gene expression traits. These analyses provide a glimpse of the potential mapping power and resolution of the CC.
Publication Title
Genetic analysis of complex traits in the emerging Collaborative Cross.
Sample Metadata Fields
Specimen part
View Samples- Saccharomyces cerevisiae
- 6 Downloadable Samples
- Affymetrix Yeast Genome S98 Array (ygs98)
Description
Prolonged cultivation of Saccharomyces cerevisiae in aerobic, glucose-limited chemostat cultures (dilution rate, 010 h1) resulted in a progressive decrease of the residual glucose concentration (from 20 to 8 mg l1 after 200 generations). This increase in the affinity for glucose was accompanied by a fivefold decrease of fermentative capacity, and changes in cellular morphology. These phenotypic changes were retained when single-cell isolates from prolonged cultures were used to inoculate fresh chemostat cultures, indicating that genetic changes were involved. Kinetic analysis of glucose transport in an evolved strain revealed a decreased Km, while Vmax was slightly increased relative to the parental strain. Apparently, fermentative capacity in the evolved strain was not controlled by glucose uptake. Instead, enzyme assays in cell extracts of the evolved strain revealed strongly decreased capacities of enzymes in the lower part of glycolysis. This decrease was corroborated by genome-wide transcriptome analysis using DNA microarrays. In aerobic batch cultures on 20 g glucose l1, the specific growth rate of the evolved strain was lower than that of the parental strain (028 and 037 h1, respectively). Instead of the characteristic instantaneous production of ethanol that is observed when aerobic, glucose-limited cultures of wild-type S. cerevisiae are exposed to excess glucose, the evolved strain exhibited a delay of 90 min before aerobic ethanol formation set in. This study demonstrates that the effects of selection in glucose-limited chemostat cultures extend beyond glucose-transport kinetics. Although extensive physiological analysis offered insight into the underlying cellular processes, the evolutionary driving force for several of the observed changes remains to be elucidated
Publication Title
Prolonged selection in aerobic, glucose-limited chemostat cultures of Saccharomyces cerevisiae causes a partial loss of glycolytic capacity.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Uniparental parthenotes are considered an unwanted byproduct of in vitro fertilization. In utero parthenote development is severely compromised by defective organogenesis and in particular by defective cardiogenesis. Although developmentally compromised, apparently pluripotent stem cells can be derived from parthenogenetic blastocysts. Here we hypothesized that nonembryonic parthenogenetic stem cells (PSCs) can be directed toward the cardiac lineage and applied to tissue-engineered heart repair. We first confirmed similar fundamental properties in murine PSCs and embryonic stem cells (ESCs), despite notable differences in genetic (allelic variability) and epigenetic (differential imprinting) characteristics. Haploidentity of major histocompatibility complexes (MHCs) in PSCs is particularly attractive for allogeneic cell-based therapies. Accordingly, we confirmed acceptance of PSCs in MHC-matched allotransplantation. Cardiomyocyte derivation from PSCs and ESCs was equally effective. The use of cardiomyocyte-restricted GFP enabled cell sorting and documentation of advanced structural and functional maturation in vitro and in vivo. This included seamless electrical integration of PSC-derived cardiomyocytes into recipient myocardium. Finally, we enriched cardiomyocytes to facilitate engineering of force-generating myocardium and demonstrated the utility of this technique in enhancing regional myocardial function after myocardial infarction. Collectively, our data demonstrate pluripotency, with unrestricted cardiogenicity in PSCs, and introduce this unique cell type as an attractive source for tissue-engineered heart repair.
Publication Title
Parthenogenetic stem cells for tissue-engineered heart repair.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 21 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The small airway epithelium (SAE) the pseudostratified epithelium that covers the majority of the human airway surface from the 6th generation to the alveoli, is the major site of lung disease caused by smoking, and the cell population that exhibits the earliest manifestations of smoking-induced disease. The focus of this study is to use RNA-Seq (massive parallel sequencing technology) to sequence all polyA+ mRNAs expressed by the SAE of healthy nonsmokers to gain new insights into the biology of the SAE, and how these cells respond to cigarette smoke. Taking advantage of RNA-Seq providing quantitative mRNA levels, that data demonstrates that while the SAE shares its transcriptome with many cell types, it has unique characteristics that are enriched in this cell population, with the mostly highly expressed genes (SCGB1A1) characteristics of Clara cells, an airway epithelial cell unique to the human small airways. Among other genes expressed by the SAE are those characteristic of ciliated and mucin-producing cells, basal cells and neuroendocrine cells. The RNA-Seq data includes identification of the highly expressed SAE transcription factors, transmembrane receptors, signaling ligands and growth factors. RNA-Seq permitted quantification of expression of highly homologous gene families, the absolute smoking-induced changes in SAE gene expression, including genes expressed at low levels, and assessment of the effect of smoking on SAE gene splicing. Together, these observations can serve as the baseline for assessment of the dysregulation of SAE gene expression in human airway disease.
Publication Title
RNA-Seq quantification of the human small airway epithelium transcriptome.
Sample Metadata Fields
Race
View Samples- Homo sapiens
- 24 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Glucocorticoids (GCs) are commonly used to treat patients suffering from lymphoid malignancies i.e. leukemia and multiple myeloma. Although GCs are known to be strong inducers of apoptosis in lymphoid cells, the molecular determinants of GC therapy resistance are poorly understood. Although GC treatment triggers important changes in gene expression, few studies have addressed the regulatory role of small regulatory microRNAs (miRNAs) in GC therapy response. Only recently, aberrant microRNA expression has been linked to the development of haematological malignancies and microRNAs have become master regulators of drug resistance. We identified GC inducible mRNA and microRNA transcription profiles in GC sensitive MM1S as compared to GC resistant MM1R cells. Transcriptome analysis revealed that GCs regulate multiple genes involved in cell cycle control, cell organization and cell death in MM1S, which remain unaffected in MM1R cells. Correspondingly, GCs selectively trigger cell death in MM1S but not in MM1R. Out of 32 microRNAs responsive to GC in MM1S cells but not in MM1R cells, mir-150 was identified as the most persistent GC responsive microRNA. Furthermore, Ingenuity Pathways Analysis (IPA) revealed that ectopic transfection of a synthetic mir-150 mimics GC therapy response in MM1S cells, associated with selective changes in mRNA levels of typical GR transactivated and transrepressed target genes. Although mir-150 largely mirrors GC responsive changes in gene expression of the transcription factor Myb, GR chaperone FKBP5, cell cycle modulator proteins (IL23A, SKP2, CDKN1A), chemokine signaling proteins (CXCR4, CX3CR1, CCL3) and mTOR/UPR stress related proteins (DDIT4, TXNIP), we also observed mir-150 selective effects on transcription factors (NR3C2 (MR), Myb, Fos, Jun, C/EBP-beta, IRF4, NFE2L1, ATF3, ATF4,), chaperone molecules HSPA8, HSP90AB1), the sodium channel SCNN1G and UPR stress proteins (TRIB3, DDIT3). Remarkably, mir-150 overexpression was not able to overcome GC therapy resistance, since we could not detect GC like effects of mir-150 in GR (NR3C1) deficient MM1R cells. Altogether GC-inducible mir-150 adds a novel complex layer of regulation for fine tuning GC specific therapeutic responses in multiple myeloma.
Publication Title
Ectopic microRNA-150-5p transcription sensitizes glucocorticoid therapy response in MM1S multiple myeloma cells but fails to overcome hormone therapy resistance in MM1R cells.
Sample Metadata Fields
Cell line, Treatment
View Samples