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GSE19537
Rattus norvegicus
53 Downloadable Samples
Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Human type 1 diabetes (T1D) arises through autoimmunity towards the insulin-producing pancreatic cells and is modeled by the BioBreeding (BB) rat. Factors associated with islet autoimmunity are dilute and difficult to directly measure in the periphery. Therefore, we previously utilized microarray-based bioassay where human T1D sera were used to induce a disease-specific gene expression signature in unrelated, healthy peripheral blood mononuclear cells (PBMC).
Publication Title
Identification of a serum-induced transcriptional signature associated with type 1 diabetes in the BioBreeding rat.
Sample Metadata Fields
No sample metadata fields
View Samples- Rattus norvegicus
- 10 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Like humans, the NOD mouse and other diabetes susceptible rat strains, T1D in BB rats is dependent on the major histocompatibility complex (MHC, insulin dependent diabetes mellitus locus 1, Iddm1) located on chromosome 20. In rats this is the HLA-DQB1 homologue RT1-B, specifically the RT1u haplotype. Our studies employ congenic derivatives of the BB rat, the DRlyp/lyp and DR+/+ strains, which differ only by the 2 Mb lyp (lymphopenia, Iddm2) region on chromosome 4. TID in the lymphopenic DRlyp/lyp rat is spontaneous and onset occurs in 100% of animals during adolescence (65.3+/-6.3 days) due to a recessive mutation within GIMAP5 (GTPase, IMAP family member 5). Gimap5 is a mitochondrial GTP-binding protein necessary for post-thymic T cell survival. The spontaneously diabetic phenotype observed in DRlyp/lyp rats is thought to be elicited through deficiency in CD4+CD25+ TREG cells as T1D in lymphopenic BB rats can be rescued through adoptive transfer of this population. Genetic variation in GIMAP5 has been associated with the development of protein-tyrosine phosphatase-2 (IA-2) autoantibodies in human T1D [28] and is significantly associated with systemic lupus erythematosus (SLE). The non-lymphopenic DR+/+ strain possesses wild-type GIMAP5 alleles and does not develop spontaneous T1D, however, T1D is inducible through administration of lymphotoxic anti-RT6 monoclonal antibody and immune activating polyinosinic polycytidylic acid (poly I:C; a ligand of toll-like receptor 3), or through viral depletion of CD4+CD25+ regulatory T (TREG) cells. Such treatments do not induce T1D in the related Wistar-Furth (WF) rats and suggest the presence of an underlying diabetic predisposition in BB rats that is phenotypically manifested upon loss of immune regulation.
Publication Title
Biobreeding rat islets exhibit reduced antioxidative defense and N-acetyl cysteine treatment delays type 1 diabetes.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 12 Downloadable Samples
- Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
Phosphatidylcholine transfer protein (PC-TP, a.k.a StarD2) is abundantly expressed in liver and is regulated by PPAR. When fed the synthetic PPAR ligand fenofibrate, Pctp-/- mice exhibited altered lipid and glucose homeostasis. Microarray profiling of liver from fenofibrate fed wild type and Pctp-/- mice revealed differential expression of a broad array of metabolic genes, as well as their regulatory transcription factors. Because its expression controlled the transcriptional activities of both PPAR and HNF4 in cell culture, the broader impact of PC-TP on nutrient metabolism is most likely secondary to its role in fatty acid metabolism.
Publication Title
Regulatory role for phosphatidylcholine transfer protein/StarD2 in the metabolic response to peroxisome proliferator activated receptor alpha (PPARalpha).
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 29 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Ewings sarcoma is highly malignant bone tumor that involves childhood and adolescent, and its nature has not been well understood. To clarify its cellular origin and the mechanisms of tumorigenesis, we used ex vivo approach to create a murine model for Ewings sarcoma. The osteochondrogenic progenitors derived from the embryonic superficial zone (eSZ, designated as FZ in the data set) of murine long bones at late gestation were purified by microdissection, introduced with EWS-FLI1 or EWS-ERG retroviruses and transplanted into nude mice. Ewings sarcoma-like small round cell sarcoma developed at 100% penetrance, whereas tumor induction was less effective when growth place (GP)-derived cells were used. The different response of gene expression to EWS-FLI1 between eSZ and GP cells suggests importance of the specific cellular context for EWS-FLI1 to induce Ewings sarcoma. The Wnt/-catenin pathway was involved in close relationship to the cellular context, with Dkk2 and Wipf1 as important downstream modulators. Furthermore, gene expression profiling revealed similarity between our models and human Ewings sarcoma. These results indicate that Ewings sarcoma originates from the embryonic osteochondrogenic progenitor.
Publication Title
Ewing's sarcoma precursors are highly enriched in embryonic osteochondrogenic progenitors.
Sample Metadata Fields
Specimen part, Time
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
A chromosomal translocation fusion gene product EWS-WT1 is the defining genetic event in Desmoplastic Small Round Cell Tumor (DSRCT), a rare but aggressive tumor with a high rate of mortality. EWS-WT1 oncogene acts as an aberrant transcription factor that drives tumorigenesis, but the mechanism by which EWS-WT1 causes tumorigenesis is not well understood. To delineate the oncogenic mechanisms, we generated the EWS-WT1 fusion in the mouse using a gene targeting (knock-in) approach, enabling physiologic expression of EWS-WT1 under the native Ews promoter. We derived mouse embryonic fibroblasts (MEFs) and performed genome-wide expression profiling to identify transcripts directly regulated by EWS-WT1. Remarkably, expression of EWS-WT1 led to a dramatic induction of many neuronal genes. Notably, a neural reprogramming factor, ASCL1 (achaete-scute complex-like 1), was highly induced by EWS-WT1 in MEFs and in primary DSRCT. Further analysis demonstrated that EWS-WT1 directly binds to the proximal promoter region of ASCL1 and activates its transcription through multiple WT1-responsive elements. Depletion of EWS-WT1 in a DSRCT cell line resulted in severe reduction in ASCL1 expression and cell viability. Remarkably, when stimulated with neuronal induction media, cells expressing EWS-WT1 expressed neural markers and generated neurite-like projections. These results demonstrate for the first time that EWS-WT1 activates neural gene expression and is capable of directing partial neuronal differentiation, likely via ASCL1. These findings suggest that stimulating DSRCT tumor cells with biological or chemical agents that promote neural differentiation might be a useful approach to develop novel therapeutics against this incurable disease.
Publication Title
EWS-WT1 oncoprotein activates neuronal reprogramming factor ASCL1 and promotes neural differentiation.
Sample Metadata Fields
Specimen part, Time
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Ewings sarcoma is highly malignant bone tumor that involves childhood and adolescent, and its nature has not been well understood. To clarify its cellular origin and the mechanisms of tumorigenesis, we used ex vivo approach to create a murine model for Ewings sarcoma. The osteochondrogenic progenitors derived from the facial zone (FZ) of murine long bones at late gestation were purified by microdissection, introduced with EWS-FLI1 or EWS-ERG retroviruses and transplanted into nude mice. Ewings sarcoma-like small round cell sarcoma developed at 100% penetrance, whereas tumor induction was less effective when growth place (GP)-derived cells were used. The different response of gene expression to EWS-FLI1 between FZ and GP cells suggests importance of the specific cellular context for EWS-FLI1 to induce Ewings sarcoma. The Wnt/-catenin pathway was involved in close relationship to the cellular context, with Dkk2 and Wipf1 as important downstream modulators. Furthermore, gene expression profiling revealed similarity between our models and human Ewings sarcoma. These results indicate that Ewings sarcoma originates from the embryonic osteochondrogenic progenitor.
Publication Title
Ewing's sarcoma precursors are highly enriched in embryonic osteochondrogenic progenitors.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 4 Downloadable Samples
Illumina HiSeq 2000
Description
Complete polarization of macrophages towards an M1-like proinflammatory and antimicrobial state requires combined action of IFN-? and LPS. Synergistic activation of canonical inflammatory NF-?B target genes by IFN-? and LPS is well appreciated, but less is known about whether IFN-? negatively regulates components of the LPS response, and how this affects polarization. A combined transcriptomic and epigenomic approach revealed that IFN-? selectively abrogates LPS-induced feedback and select metabolic pathways by suppressing TLR4-mediated activation of gene enhancers. In contrast to superinduction of inflammatory genes via enhancers that harbor IRF sequences and bind STAT1, IFN-?-mediated repression targeted enhancers with STAT sequences that bound STAT3. TLR4-activated IFN-?-suppressed enhancers comprised two subsets distinguished by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin, and were functionally inactivated by IFN-?. These findings reveal that IFN-? suppresses feedback inhibitory and metabolic components of the TLR response to achieve full M1 polarization, and provide insights into mechanisms by which IFN-? selectively inhibits TLR4-induced transcription. Overall design: RNA-seq analysis of transcriptional changes in human macrophages that were cultured with or without IFN-? and then stimulated with LPS
Publication Title
IFN-γ selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate macrophage activation.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Homo sapiens
- 14 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We have used an agnostic approach to identify drug combinations by using combination high throughput screening (cHTS) technology and make the surprising discovery that adenosine A2A and beta-2 adrenergic receptor agonists are highly synergistic, selective and novel agents that enhance glucocorticoid activity in B-cell malignancies.
Publication Title
Adenosine A2A and beta-2 adrenergic receptor agonists: novel selective and synergistic multiple myeloma targets discovered through systematic combination screening.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
ALS is a uniformly fatal neurodegenerative disease in which motor neurons in the spinal cord and brain stem are selectively lost. Individual motor - groups of motor neurons innervating single muscles - show widely varying degrees of disease resistance: in the final stages of ALS, nearly all voluntary movement is lost but eye movement and eliminative and sexual functions remain relatively unimpaired. These functions are controlled by motor neurons of the oculomotor (III), trochlear (IV) and abducens (VI) nuclei in the midbrain and brainstem, and by Onufs nucleus in the lumbosacral spinal cord, respectively. Correspondingly, in ALS autopsies the oculomotor and Onufs nuclei are almost completely preserved. We used microarray profiling of isolated wildtype mouse motor neurons to identify genes whose expression was characteristic of both oculomotor and Onufs nuclei but not of vulnerable lumbar spinal neurons, or vice versa.
Publication Title
Neuronal matrix metalloproteinase-9 is a determinant of selective neurodegeneration.
Sample Metadata Fields
Sex, Specimen part
View Samples- Danio rerio
- 6 Downloadable Samples
- IlluminaHiSeq2500
Description
We report how the zebrafish melanoma cell line ZMEL1 changes after 4 month exposure to the BRAF inhibitor PLX4032 (1uM) Overall design: Examination of ZMEL1 vs. ZMELR1 cells growing in vitro
Publication Title
Melanoma genome evolution across species.
Sample Metadata Fields
No sample metadata fields
View Samples