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GSE40102
Homo sapiens
24 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Cell-based models of many neurological and psychiatric diseases, established by reprogramming patient somatic cells into human induced pluripotent stem cells (hiPSCs), have now been reported. While numerous reports have demonstrated that neuronal cells differentiated from hiPSCs are electrophysiologically active mature neurons, the age of these cells relative to cells in the human brain remains unresolved. Comparisons of gene expression profiles of hiPSC-derived neural progenitor cells (NPCs) and neurons to the Allen BrainSpan Atlas indicate that hiPSC neural cells most resemble first trimester neural tissue. Consequently, we posit that hiPSC-derived neural cells may most accurately be used to model the early developmental defects that contribute to disease predisposition rather than the late features of the disease. Though the characteristic symptoms of schizophrenia (SCZD) generally appear late in adolescence, it is now thought to be a neurodevelopmental condition, often predated by a prodromal period that can appear in early childhood. Postmortem studies of SCZD brain tissue typically describe defects in mature neurons, such as reduced neuronal size and spine density in the prefrontal cortex and hippocampus, but abnormalities of neuronal organization, particularly in the cortex, have also been reported. We postulated that defects in cortical organization in SCZD might result from abnormal migration of neural cells. To test this hypothesis, we directly reprogrammed fibroblasts from SCZD patients into hiPSCs and subsequently differentiated these disorder-specific hiPSCs into NPCs. SCZD hiPSC differentiated into forebrain NPCs have altered expression of a number of cellular adhesion genes, reduced WNT signaling and aberrant cellular migration.
Publication Title
Phenotypic differences in hiPSC NPCs derived from patients with schizophrenia.
Sample Metadata Fields
Sex, Specimen part, Disease, Disease stage
View Samples- Homo sapiens
- 10 Downloadable Samples
IlluminaGenomeAnalyzerII
Description
Pancreatic beta-cell dysfunction and death are central in the pathogenesis of type 2 diabetes. Saturated fatty acids cause beta-cell failure and contribute to diabetes development in genetically predisposed individuals. Here we used RNA-sequencing to map transcripts expressed in five palmitate-treated human islet preparations, observing 1,325 modified genes. Palmitate induced fatty acid metabolism and endoplasmic reticulum (ER) stress. Functional studies identified novel mediators of adaptive ER stress signaling. Palmitate modified genes regulating ubiquitin and proteasome function, autophagy and apoptosis. Inhibition of autophagic flux and lysosome function contributed to lipotoxicity. Palmitate inhibited transcription factors controlling beta-cell phenotype including PAX4 and GATA6. 59 type 2 diabetes candidate genes were expressed in human islets, and 11 were modified by palmitate. Palmitate modified expression of 17 splicing factors and shifted alternative splicing of 3,525 transcripts. Ingenuity Pathway Analysis of modified transcripts and genes confirmed that top changed functions related to cell death. DAVID analysis of transcription binding sites in palmitate-modified transcripts revealed a role for PAX4, GATA and the ER stress response regulators XBP1 and ATF6. This human islet transcriptome study identified novel mechanisms of palmitate-induced beta-cell dysfunction and death. The data point to crosstalk between metabolic stress and candidate genes at the beta-cell level. Overall design: 5 human islet of Langerhans preparations examined under 2 conditions (control and palmitate treatment)
Publication Title
RNA sequencing identifies dysregulation of the human pancreatic islet transcriptome by the saturated fatty acid palmitate.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina MouseWG-6 v2.0 expression beadchip
Description
Members of the CUG-BP, Elav-like family (CELF) regulate alternative splicing in the heart. In MHC-CELFdelta transgenic mice, CELF splicing activity is inhibited postnatally in heart muscle via expression of a nuclear dominant negative CELF protein under an a-myosin heavy chain promoter. MHC-CELFdelta mice develop dilated cardiomyopathy characterized by alternative splicing defects, enlarged hearts, and severe contractile dysfunction. In this study, gene expression profiles in the hearts of wild type, high- and low-expressing lines of MHC-CELFdelta mice were compared using microarrays. Gene ontology and pathway analyses identified contraction and calcium signaling as the most affected processes. Network analysis revealed that the serum response factor (SRF) network is highly affected. Downstream targets of SRF were up-regulated in MHC-CELFdelta mice compared to the wild type, suggesting an increase in SRF activity. Although SRF levels remained unchanged, known inhibitors of SRF activity were down-regulated. These results suggest a role for CELF-mediated alternative splicing in the regulation of contractile gene expression, achieved in part through modulating the activity of SRF, a key cardiac transcription factor.
Publication Title
Gene expression analyses implicate an alternative splicing program in regulating contractile gene expression and serum response factor activity in mice.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Gallus gallus
- 15 Downloadable Samples
- Illumina HiSeq 2000
Description
We report on the regulation of transcripts following siRNA-mediated depletion of an RNA binding protein, CELF1, in primary chicken embryonic cardiomyocytes in culture. Overall design: Cultured chicken primary embryonic cardiomyocytes (isolated from embryonic day 8 hearts) were transfected with siRNA against CELF1 (n=3) or mock transfected (n=3) at 24 hours in culture.
Publication Title
Identification of Targets of CUG-BP, Elav-Like Family Member 1 (CELF1) Regulation in Embryonic Heart Muscle.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
AEBP1 has been identified as a transcriptional repressor playing a
Publication Title
Identification of genomic targets of transcription factor AEBP1 and its role in survival of glioma cells.
Sample Metadata Fields
Cell line
View Samples- Danio rerio
- 12 Downloadable Samples
- Affymetrix Zebrafish Genome Array (zebrafish)
Description
Exposures to dioxin, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) cause a wide array of toxicities in vertebrates and is mostly considered to be mediated through the inappropriate activation of the aryl hydrocarbon receptor (Ahr) signaling pathway. Although transcriptional regulation by Ahr is widely studied, the molecular mechanisms responsible for the adverse outcomes after Ahr activation are largely unknown. To identify the important events downstream of AHR activation that play an actual role in the toxic responses, we employed the zebrafish caudal fin regeneration models since Ahr activation blocks the regenerative process. Zebrafish regenerate their caudal fins by an orchestrated progression of cell migration, differentiation and proliferation controlled by a multitude of signaling pathways. This complex process was exploited as an in vivo platform to identify cross talk between Ahr and other signaling pathways. Global genomic analysis was performed in the larval regenerating fin tissue after exposure to TCDD in order to identify genes differentially regulated after Ahr activation. Comparative toxicogenomic analysis revealed that both adult and larval fins respond to TCDD during regeneration with mis-expression of Wnt signaling pathway members and Wnt target genes.
Publication Title
Crosstalk between AHR and Wnt signaling through R-Spondin1 impairs tissue regeneration in zebrafish.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 165 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
To investigate the cellular responses induced by air pollution exposures, we performed genome-wide gene expression microarray analysis using whole blood RNA sampled at three time-points across the work weeks of 63 non-smoking employees in the trucking industry. Our objective was to identify the genes and gene networks differentially activated in response to micro-environmental measures of occupational exposure to three pollutants: PM2.5 (particulate matter 2.5 microns in diameter) and elemental carbon (EC) and organic carbon (OC).
Publication Title
Gene expression network analyses in response to air pollution exposures in the trucking industry.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Inflammation has a causal role in many cancers. In prostate cancers, epidemiological data suggest a link between prostatitis and subsequent cancer development, but a proof for this concept in a tumor model has been lacking. A constitutively active version of the IkappaB kinase 2 (IKK2), the molecule activated by a plethora of inflammatory stimuli, was expressed specifically in the prostate epithelium. Signaling of the IKK2/NF-kappaB axis was insufficient for transformation of prostate tissue. However, while PTEN+/- epithelia exhibited intraepithelial neoplasias only recognizable by nuclear alterations, additional IKK2 activation led to an increase in tumor size and formation of cribriform structures and to a fiber increase in the fibroblastic stroma. This phenotype was coupled with inflammation in the prostate gland characterized by infiltration of granulocytes and macrophages. Molecular characterization of the tissues showed a specific loss of smooth muscle markers as well as expression of chemokines attracting immune cells. Isolation of epithelial and stromal cells showed differential chemokine expression by these cells. Correlation studies showed the inflammatory phenotype coupled to loss of smooth muscle in infiltrated glands, but maintenance of the phenotype in glands where inflammation had decreased. Despite the loss of the smooth muscle barrier, tumors were not invasive in a stable genetic background. Data mining revealed that smooth muscle markers are downregulated in human prostate cancers and literature data show that loss of these markers in primary tumors is associated with subsequent metastasis. Our data show that loss of smooth muscle and invasiveness of the tumor are not coupled. Thus, inflammation during early steps of tumorigenesis can lead to increased tumor size and a potential change in the subsequent metastatic potential, but the tumor requires an additional transformation to become a carcinoma.
Publication Title
Persistent inflammation leads to proliferative neoplasia and loss of smooth muscle cells in a prostate tumor model.
Sample Metadata Fields
Age, Specimen part
View Samples- Pseudomonas aeruginosa
- 4 Downloadable Samples
- Affymetrix Pseudomonas aeruginosa Array (paeg1a)
Description
Quorum sensing (QS) is a mechanism of bacterial gene regulation in response to increases in population density. Production of small molecule QS signals, their accumulation within a diffusion-limited environment and their binding to the LuxR-type receptor trigger QS-controlled gene regulatory cascades. QS pathways mediated by acylhomoserine lactones (AHLs) in Gram-negative bacteria are the best studied. In Pseudomonas aeruginosa, for example, binding of AHLs to their cognate receptors (LasR, RhlR) controls production of virulence factors, pigments, antibiotics and other behaviors important for its interactions with eukaryotic hosts and other bacteria. We isolated a new small cyclopropane-containing fatty acid, lyngbyoic acid (1), as a major metabolite of the marine cyanobacterium, Lyngbya sp., collected off Fort Pierce, Florida. The structure of 1 was determined by NMR, MS and optical rotation. We screened 1 against four reporters based on AHL receptors from Vibrio fischeri (LuxR), Aeromonas hydrophila (AhyR), Agrobacterium tumefaciens (TraR) and P. aeruginosa (LasR) and found that 1 most strongly affected LasR. We show, by using a defined set of reporters, that compound 1 acts both through the AHL-binding site of LasR and independent of it. We also show that 1 reduces pyocyanin and LasB, both on the protein and transcript level, in wild-type P. aeruginosa, and that 1 directly inhibits LasB enzymatic activity. Conversely, dodecanoic acid (11) increased pyocanin and LasB, demonstrating that 1 is a tagged fatty acid potentially resistant to -oxidation.
Publication Title
Lyngbyoic acid, a "tagged" fatty acid from a marine cyanobacterium, disrupts quorum sensing in Pseudomonas aeruginosa.
Sample Metadata Fields
No sample metadata fields
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