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SRP007403
Homo sapiens
2 Downloadable Samples
IlluminaGenomeAnalyzer
Description
Regulation of cell-cell junction formation and regulation of cell migration were enriched among EMT (Epithelial-Mesenchymal Transition)-associated alternatively splicing events. Our analysis suggested that most EMT-associated alternative splicing events are regulated by one or more members of the RBFOX, MBNL, CELF, hnRNP or ESRP classes of splicing factors. The EMT alternative splicing signature was confirmed in human breast cancer cell lines, which could be classified into basal and luminal subtypes based exclusively on their EMTassociated splicing pattern. Expression of EMT-associated alternative mRNA transcripts was also observed in primary breast cancer samples, indicating that EMT-dependent splicing changes occur commonly in human tumors. The functional significance of EMT-associated alternative splicing was tested by expression of the epithelial-specific splicing factor ESRP1 or depletion of RBFOX2 in mesenchymal cells, both of which elicited significant changes in cell morphology and motility towards an epithelial phenotype, suggesting that splicing regulation alone can drive critical aspects of EMT-associated phenotypic changes. The molecular description obtained here may aid in the development of new diagnostic and prognostic markers for analysis of breast cancer progression. Overall design: Examination of transcriptomes of HMLE/Twist-ER before and after induction of EMT by tamoxifen
Publication Title
An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 12 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Rheumatoid arthritis is an autoimmune disease in which joint inflammation lead to progressive cartilage and bone destruction. Matrix metalloproteinases (MMP) implicated in homeostasis of extracellular matrix (ECM) play a central role in cartilage degradation. The aim of this study was to investigate the role of MMP-8 (collagenase-2) suppression in the K/BxN serum-transfer arthritis model.
Publication Title
Matrix metalloproteinase-8 deficiency increases joint inflammation and bone erosion in the K/BxN serum-transfer arthritis model.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Spheroids are 3D multi-cell aggregates formed in non-addherent culture conditions. In ovarian cancer (OC), they serve as a vehicle for cancer cell dissemination in the peritoneal cavity. We investigated genes and networks upregulated in three dimensional (3D) versus two-dimensional (2D) culture conditions by Affymetrix gene expression profiling and identified ALDH1A1, a cancer stem cell marker as being upregulated in OC spheroids. Network analysis confirmed ALDH1A1 upregulation in spheroids in direct connection with elements of the -catenin pathway. A parallel increase in the expression levels of -catenin and ALDH1A1 was demonstrated in spheroids vs. monolayers an in successive spheroid generations by using OC cell liness and primary OC cells. The percentage of Aldefluor positive cells was significantly higher in spheroids vs. monolayers in IGROV1, A2780, SKOV3, and primary OC cells. B-catenin knock-down decreased ALDH1A1 expression and chromatin immunoprecipitation demonstrated that -catenin directly binds to the ALDH1A1 promoter. Both siRNA mediated -catenin knock-down and a novel ALDH1A1 small molecule enzymatic inhibitor described here for the first time, decreased the number of OC spheroids (p<0.001) and cell viability. These data strongly support the role of -catenin regulated ALDH1A1 in the maintenance of OC spheroids and of a stem cell phenotype and propose new ALDH1A1 inhibitors targeting this cell population.
Publication Title
β-Catenin-regulated ALDH1A1 is a target in ovarian cancer spheroids.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 9 Downloadable Samples
- Illumina HiSeq 2500
Description
The rapid transit from hypoxia to normoxia in the lung that follows the first breath in newborn mice coincides with alveolar macrophage (AM) differentiation. However, whether sensing of oxygen affects AM maturation and function has not been previously explored. We have generated mice whose AMs show a deficient ability to sense oxygen after birth by deleting Vhl, a negative regulator of HIF transcription factors, in the CD11c compartment (CD11c?Vhl mice). VHL-deficient AMs show an immature-like phenotype and an impaired self-renewal capacity in vivo that persists upon culture ex vivo. VHL-deficient phenotype is intrinsic in AMs derived from monocyte precursors in mixed bone marrow chimeras. Moreover, unlike control Vhlfl/fl, AMs from CD11c?Vhl mice do not revert pulmonary alveolar proteinosis when transplanted into Csf2rb-/- mice, demonstrating that VHL contributes to AM-mediated surfactant clearance. Thus, our results suggest that optimal AM terminal differentiation, self-renewal, and homeostatic function requires their oxygen sensing capacity. Overall design: BAL AMs were pooled from 5-7 age and sex-matched mice per genotype and further purified by positive selection with anti-CD11c-microbeads (Miltenyi Biotec), following manufacturer's instructions. Cell lysis was performed with buffer RLT (Qiagen), containing 10µ/ml ß-mercaptoethanol and RNA was isolated with RNeasy Plus Mini Kit (Qiagen). RNA concentration and integrity were determined with an Agilent 2100 Bioanalyzer (Caliper Life Science). Samples with RNA integrity values > 8 were further processed. A total of 3 pools per genotype were used for RNA Seq.
Publication Title
Von Hippel-Lindau Protein Is Required for Optimal Alveolar Macrophage Terminal Differentiation, Self-Renewal, and Function.
Sample Metadata Fields
Treatment, Subject
View Samples- Homo sapiens
- 6 Downloadable Samples
- NextSeq 500
Description
Endogenous retroviruses (ERVs) have accumulated in vertebrate genomes and contribute to the complexity of gene regulation. KAP1 represses ERVs during development by its recruitment to their repetitive sequences through KRAB-zinc finger proteins (KZNFs), but little is known about the regulation of ERVs in differentiated cells. We observed that KAP1 repression of HERVK14C was conserved in differentiated human cells and performed KAP1 knockout to obtain an overview of KAP1 function. Our results show that KAP1 represses ERVs (including HERV-T and HERV-S) and ZNFs, both of which overlap with KAP1 binding sites and H3K9me3 in multiple cell types. Furthermore, this pathway is functionally conserved in primary peripheral blood mononuclear cells. Cytosine methylation that acts on KAP1-regulated loci is necessary to prevent an interferon response, and KAP1-depletion leads to activation of some interferon-stimulated genes. Finally, loss of KAP1 leads to a decrease in H3K9me3 enrichment at ERVs and ZNFs and an RNA-sensing response mediated through MAVS signaling. These data indicate that the KAP1-KZNF pathway contributes to genome stability and innate immune control in differentiated human cells. Overall design: Dissection of which transposons and genes KAP1 regulates in differentiated human cells
Publication Title
KAP1 regulates endogenous retroviruses in adult human cells and contributes to innate immune control.
Sample Metadata Fields
Cell line, Subject
View Samples- Homo sapiens
- 92 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Rationale: The acute respiratory distress syndrome is refractory to pharmacological intervention. Inappropriate activation of alveolar neutrophils is believed to underpin this diseases complex pathophysiology, yet these cells have been little studied.
Publication Title
Acute Respiratory Distress Syndrome Neutrophils Have a Distinct Phenotype and Are Resistant to Phosphoinositide 3-Kinase Inhibition.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Time
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Diffuse large B-cell lymphoma (DLBCL) has striking clinical and molecular variability. Although a more precise identification of the multiple determinants of this variability is still under investigation, there is a consensus that high-clinical-risk DLBCL cases require a risk-adapted therapy, since intensification of chemotherapy with autologous stem-cell transplantation (ASCT) has been shown to improve the prognosis for high-risk patients in randomised clinical trials.
Publication Title
Identification of biological markers of sensitivity to high-clinical-risk-adapted therapy for patients with diffuse large B-cell lymphoma.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 18 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Protein Syndesmos is a novel RNA-binding protein that regulates primary cilia formation.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 48 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Bacterial infections cause exaserbations in COPD. Study conducted to asses the effect of Nemiralisib, a PI3Kdelta inhibitor, on S. pneumoniae infected mice
Publication Title
PI3Kδ hyper-activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody-independent manner.
Sample Metadata Fields
Specimen part, Time
View Samples- Rattus norvegicus
- 17 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Hepatic fibrosis, the wound-healing response to repeated liver injury, ultimately leads to cirrhosis. There is an urgent need to develop effective antifibrotic therapies. Ghrelin (encoded by Ghrl) is an orexigenic hormone that has pleiotrophic functions including protection against cell death1. Here we investigate whether ghrelin modulates liver fibrosis and protects from acute liver injury. Recombinant ghrelin reduced the fibrogenic response to prolonged bile duct ligation in rats. This effect was associated with decreased liver injury and myofibroblast accumulation as well as attenuation of the altered gene expression profile. Ghrelin also reduced fibrogenic properties in cultured hepatic stellate cells. Moreover, Ghrl-/- mice developed exacerbated hepatic fibrosis and liver damage after chronic injury. Ghrelin also protected rat livers from acute liver injury and reduced the extent of oxidative stress and the inflammatory response. In patients with chronic liver diseases, ghrelin serum levels decreased in those with advanced fibrosis and hepatic expression of the ghrelin gene correlated with expression of fibrogenic genes. Finally, in patients with chronic hepatitis C, single nucleotide polymorphisms of the ghrelin gene (-994CT and 604GA) influenced the progression of liver fibrosis. We conclude that ghrelin exerts antifibrotic effects on the liver and may represent a novel antifibrotic therapy.
Publication Title
Ghrelin attenuates hepatocellular injury and liver fibrogenesis in rodents and influences fibrosis progression in humans.
Sample Metadata Fields
No sample metadata fields
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