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GSE19737
Homo sapiens
5 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We used Affymetrix HG U133 Plus 2.0 GeneChips to compare the transcriptome of miR-145-overexpressing MDA-MB-231 cells against negative control miRNA precursor-transfected cells.
Publication Title
miR-145-dependent targeting of junctional adhesion molecule A and modulation of fascin expression are associated with reduced breast cancer cell motility and invasiveness.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
The development of insulin resistance is strongly associated with accumulation of intracellular lipid in tissues outside of adipose including skeletal muscle, liver and heart. In obese humans, intramyocellular lipid (IMCL) is negatively correlated with whole body insulin sensitivity. The skeletal myocyte imports fatty acids (FA) into the cell from circulating free fatty acids or lipoprotein particles such as VLDL, to support energy production. Once transported into the cell, FAs are oxidized for ATP production, used to build membranes, or stored as triglyceride. However, in the long term, increased delivery of fatty acids can exceed mitochondrial oxidative capacity and set the stage for a vicious cycle of cellular lipotoxicity. We have recently identified a novel small molecule inhibitor of lipid accumulation in skeletal mycytes termed SBI-477. Microarray transcriptomics was performed in primary human skeletal myotubes following oleate loading and treatment with SBI-477. This was also compared to A922500, a diacylglycerol transferase 1 (DGAT1) inhibitor. SBI-477 treatment reversed many of the transcriptomic effects of oleate loading in these cells but also produced a transcriptomic profile distinct from the DGAT1 inhibitor.
Publication Title
MondoA coordinately regulates skeletal myocyte lipid homeostasis and insulin signaling.
Sample Metadata Fields
Treatment
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder caused by mutations in MECP2, encoding methyl-CpG binding protein 2. MeCP2 is a transcriptional repressor elevated in mature neurons and is predicted to be required for neuronal maturation by regulating multiple target genes. Identifying primary gene targets in either Mecp2-deficient mice or human RTT brain has proven to be difficult, perhaps because of the transient requirement for MeCP2 during neuronal maturation. In order to experimentally control the timing of MeCP2 expression and deficiency during neuronal maturation, human SH-SY5Y cells undergoing mature neuronal differentiation were transfected with methylated MeCP2 oligonucleotide decoy to disrupt the binding of MeCP2 to endogenous targets. Genome-wide expression microarray analysis identified all four known members of the inhibitors of differentiation or inhibitors of DNA binding (ID1, ID2, ID3 and ID4) subfamily of helix-loop-helix (HLH) genes as novel neuronal targets of MeCP2. Chromatin immunoprecipitation analysis confirmed binding of MeCP2 near or within the promoters of ID1, ID2 and ID3, and quantitative RT-PCR confirmed increased expression of all four Id genes in Mecp2-deficient mouse brain. All four ID proteins were significantly increased in Mecp2-deficient mouse and human RTT brain using immunofluorescence and laser scanning cytometric analyses. Because of their involvement in cell differentiation and neural development, ID genes are ideal primary targets for MeCP2 regulation of neuronal maturation that may explain the molecular pathogenesis of RTT.
Publication Title
Inhibitors of differentiation (ID1, ID2, ID3 and ID4) genes are neuronal targets of MeCP2 that are elevated in Rett syndrome.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 10 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Voluntary exercise reduces the risk of cancer and lowers the risk of disease recurrence. Yet the mechanisms for this protection remain to be elucidated. Here we demonstrate that exercise halves tumor growth through an exercise-dependent mobilization and intratumoral infiltration of NK cells in malignant melanoma. Using voluntary wheel running, we show that exercise prior to and during B16 tumor challenge reduced tumor growth by 67%, and this reduction was associated with increased inflammation and immune cell infiltrates, especially NK cells, in the tumors from exercising mice. Depletion of NK cells blunted the exercise-dependent reduction in tumor growth. Moreover, during exercise, NK cells were engaged through an epinephrine-dependent mobilization to the circulation and redistributed to peripheral tissues through an IL-6 dependent mechanism. This study highlights the importance of exercise-dependent immune regulation in the control of malignant melanoma
Publication Title
Voluntary Running Suppresses Tumor Growth through Epinephrine- and IL-6-Dependent NK Cell Mobilization and Redistribution.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 3 Downloadable Samples
Illumina Genome Analyzer II
Description
In adult cancers, epigenetic changes and aberrant splicing of the DNMT3B is commonly observed, and the pattern of gene methylation and expression has been shown to be modified by DNMT3B7, a truncated protein of DNMT3B. Much less is known about the mechanism of epigenetic changes in the pediatric cancer neuroblastoma. To investigate if aberrant DNMT3B transcripts alter DNA methylation, gene expression and tumor phenotype in neuroblastoma, we measured DNMT3B isoform expression in primary tumors and cell lines. Higher levels of DNMT3B7 were detected in differentiated ganglioneuroblastomas compared to undifferentiated neuroblastomas, suggesting that expression of DNMT3B7 may induce a less clinically aggressive tumor phenotype. To test this hypothesis, we investigated the effects of forced DNMT3B7 in neuroblastoma cells. We found that DNMT3B7 expression significantly inhibited neuroblastoma cell proliferation in vitro, and in neuroblastoma xenografts, DNMT3B7 decreased angiogenesis and tumor growth. DNMT3B7-positive cells had higher levels of total genomic methylation, and RNA-sequencing revealed a dramatic decrease in expression of FOS and JUN family members, AP1 complex components. Consistent with the established antagonistic relationship between AP1 expression and retinoic acid receptor activity, decreased proliferation and increased differentiation was seen in the DNMT3B7-expressing neuroblastoma cells following treatment with all trans retinoic acid (ATRA) compared to controls. Our results demonstrate that high levels of DNMT3B7 modify the epigenome in neuroblastoma cells, induce changes in gene expression, inhibit tumor growth, and increase sensitivity to ATRA. Further knowledge regarding mechanisms by which DNMT3B7 regulates gene methylation may ultimately lead to the development of therapeutic strategies that reverse the epigenetic aberrations that drive neuroblastoma pathogenesis. Overall design: DNMT3B7, a truncated DNMT3B isoform, was stably transfected into an N-type neuroblastoma cell line (LA1-55n) using a Tet-off inducible system. DNMT3B7 expressing cells were compared to vector control cells after 21 days of induction.
Publication Title
Truncated DNMT3B isoform DNMT3B7 suppresses growth, induces differentiation, and alters DNA methylation in human neuroblastoma.
Sample Metadata Fields
Cell line, Subject
View Samples- Homo sapiens
- 116 Downloadable Samples
Description
Skeletal muscle is one of the primary tissues involved in the development of type 2 diabetes (T2D). Obesity is tightly associated with T2D, making it challenging to isolate specific effects attributed to the disease alone. By using an in vitro myocyte model system we were able to isolate the inherent properties retained in myocytes originating from donor muscle precursor cells, without being confounded by varying extracellular factors present in the in vivo environment of the donor. We generated and characterized transcriptional profiles of myocytes from 24 human subjects, using a factorial design with two levels each of the factors T2D (healthy or diseased) and obesity (non-obese or obese), and determined the influence of each specific factor on genome-wide transcription. We identified a striking similarity of the transcriptional profiles associated independently with T2D or obesity. Obesity thus presents an inherent phenotype in skeletal myocytes, similar to that induced by T2D. Through bioinformatics analysis we found a candidate epigenetic mechanism, H3K27me3 histone methylation, mediating the observed transcriptional signatures. Functional characterization of the expression profiles revealed dysregulated myogenesis and down-regulated muscle function in connection with T2D and obesity, as well as up-regulation of genes involved in inflammation and the extracellular matrix. Further on, we identified a metabolite subnetwork involved in sphingolipid metabolism and affected by transcriptional up-regulation in T2D. Collectively, these findings pinpoint transcriptional changes that are hard-wired in skeletal myocytes in connection with both obesity and T2D. Overall design: Isolated skeletal muscle precursor cells from 24 males and females (6 normal glucose tolerant, 6 obese, 6 type 2 diabetic, and 6 obese and type 2 diabetic) were differentiated in vitro and stimulated with insulin. RNA from fully differentiated myotubes sampled at 0, 0.5, 1, and 2 hours after insulin stimulation was quantified using RNA-seq (96 samples in total). The 6 base-line (0h) samples from normal glucose tolerant individuals are available under the submission GSE63887, the remaining 90 samples are contained in this submission.
Publication Title
Type 2 diabetes and obesity induce similar transcriptional reprogramming in human myocytes.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 7 Downloadable Samples
- IlluminaHiSeq2500, IlluminaHiSeq2000
Description
Skeletal myocytes are metabolically active and susceptible to insulin resistance, thus implicated in type 2 diabetes (T2D). This complex disease involves systemic metabolic changes and their elucidation at the systems level requires genome-wide data and biological networks. Genome-scale metabolic models (GEMs) provide a network-context to integrate high-throughput data. We generated myocyte-specific RNA-seq data and investigated their correlation with proteome data. These data were then used to reconstruct a comprehensive myocyte GEM. Next, we performed a meta-analysis of six studies comparing muscle transcription in T2D versus healthy subjects. Transcriptional changes were mapped on the myocyte GEM, revealing extensive transcriptional regulation in T2D, particularly around pyruvate oxidation, branched-chain amino acid catabolism, and tetrahydrofolate metabolism, connected through the down-regulated dihydrolipoamide dehydrogenase. Strikingly, the gene signature underlying this metabolic regulation successfully classifies the disease state of individual samples, suggesting that regulation of these pathways is a ubiquitous feature of myocytes in response to T2D. Overall design: Isolated skeletal muscle precursor cells from six normal glucose tolerant and non-obese males and females were differentiated in vitro. RNA from fully differentiated myotubes was sequenced using RNA-seq.
Publication Title
Type 2 diabetes and obesity induce similar transcriptional reprogramming in human myocytes.
Sample Metadata Fields
No sample metadata fields
View Samples- Rattus norvegicus
- 19 Downloadable Samples
- Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
A recent two-year NTP cancer bioassay showed a marked increase in the incidence of malignant mesothelioma arising from the tunica vaginalis in male Fischer 344/N rats exposed to Vinylidene chloride (VDC). Aged male F344/N rats are prone to developing spontaneous peritoneal mesotheliomas, which also arise predominantly from the tunica vaginalis of the testes. A definitive mechanism for the observed increased incidence in VDC-exposed rats is unknown. Investigation of the molecular alterations that occur in mesotheliomas from vehicle control and VDC-exposed rats may provide insight into their pathogenesis, as well enable a better understanding regarding the mechanisms underlying chemically induced mesothelioma in rodents. Mesothelial cell function represents a complex interplay of pathways related to host defense mechanisms and maintenance of cellular homeostasis. Global gene expression profiles of spontaneous mesotheliomas from vehicle control male F344/N rats from various two-year National Toxicology Program carcinogenicity bioassays were compared to mesotheliomas from VDC-exposed rats to characterize the molecular features that are present in mesotheliomas from VDC-exposed animals, and to elucidate tumor-specific gene expression profiles. The resulting gene expression pattern showed that mesotheliomas from VDC-exposed animals are genomically very different from spontaneous tumors; while both tumor types are characterized by alterations in gene expression associated with carcinogenic pathways (oncogenes, tumor suppressor genes, growth factors, etc.), mesotheliomas from VDC-exposed animals are associated with increased dysreguation of immune pathways and inflammatory mediators. Alterations in these pathways may suggest a pro-inflammatory and immune dysfunction signature as one mechanism in the observed increased incidence of these tumors in VDC-exposed animals.
Publication Title
Spontaneous mesotheliomas in F344/N rats are characterized by dysregulation of cellular growth and immune function pathways.
Sample Metadata Fields
Disease
View Samples- Mus musculus
- 18 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Vinylidene Chloride has been widely used in the production of plastics and flame retardants. Exposure of B6C3F1 to VDC in the 2-year National Toxicology Program carcinogenicity bioassay resulted in a dose-dependent increase in renal cell hyperplasias, adenomas, and carcinomas (RCCs). Global gene expression analysis showed overrepresentation of pathways associated with chronic xenobiotic and oxidative stress in RCCs from VDC-exposed B6C3F1 mice, as well as cMyc overexpression and dysregulation of Tp53 cell cycle checkpoint and DNA damage repair pathways. Trend analysis comparing RCC, VDC-exposed kidney, and vehicle control kidney showed a conservation of pathway dysregulation in terms of overrepresentation of xenobiotic and oxidative stress, and DNA damage and cell cycle checkpoint pathways in both VDC-exposed kidney and RCC, suggesting that these mechanisms play a role in the development of RCC in VDC-exposed mice.
Publication Title
Renal Cell Carcinomas in Vinylidene Chloride-exposed Male B6C3F1 Mice Are Characterized by Oxidative Stress and TP53 Pathway Dysregulation.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Genome-wide profiling identifies a DNA methylation signature that associates with TET2 mutations in diffuse large B-cell lymphoma.
Sample Metadata Fields
Specimen part
View Samples