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SRP106195
Homo sapiens
179 Downloadable Samples
Illumina HiSeq 2000
Description
Progressive failure of insulin-producing beta cells is the central event leading to diabetes, yet the signalling networks controlling beta cell fate remain poorly understood. Here we show that SRp55, a splicing factor regulated by the diabetes susceptibility gene GLIS3, has a major role in maintaining function and survival of human beta cells. RNA-seq analysis revealed that SRp55 regulates the splicing of genes involved in cell survival and death, insulin secretion and JNK signalling. Specifically, SRp55-mediated splicing changes modulate the function of the pro-apoptotic proteins BIM and BAX, JNK signalling and endoplasmic reticulum stress, explaining why SRp55 depletion triggers beta cell apoptosis. Furthermore, SRp55 depletion inhibits beta cell mitochondrial function, explaining the observed decrease in insulin release. These data unveil a novel layer of regulation of human beta cell function and survival, namely alternative splicing modulated by key splicing regulators such as SRp55 that may crosstalk with candidate genes for diabetes. Overall design: Five independent preparations of EndoC-ßH1 cells exposed to control (siCTL) or SRp55 (siSR#2) siRNAs
Publication Title
SRp55 Regulates a Splicing Network That Controls Human Pancreatic β-Cell Function and Survival.
Sample Metadata Fields
Treatment, Subject
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- Homo sapiens
- 29 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The aim of our study was to identify gene expression profiles of ductal and lobular carcinomas in relation to normal ductal and lobular cells. We examined ten mastectomy specimens from postmenopausal breast cancer patients. Ductal and lobular tumor and normal cells were microdissected from cryosections. Fifty nanograms of total RNA were amplified and labeled by PCR and in vitro transcription. GCOS pairwise comparison algorithm and rank products have identified multiple genes that are differentially expressed in comparisons between ductal and lobular tumor and normal cell types. The results suggest that these genes are involved in epithelial-mesenchymal transition, TGFbeta and Wnt signaling. These changes are present in both tumor types but appear to be more prominent in lobular carcinomas.
Publication Title
Novel markers for differentiation of lobular and ductal invasive breast carcinomas by laser microdissection and microarray analysis.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 228 Downloadable Samples
- Illumina HiSeq 1500
Description
Tumor relapse is associated with dismal prognosis, but responsible biological principles remain incompletely understood. To isolate and characterize relapse-inducing cells, we used genetic engineering and proliferation-sensitive dyes in patient-derived xenografts of acute lymphoblastic leukemia (ALL). We identified a rare subpopulation that resembled relapse-inducing cells with combined properties of long-term dormancy, treatment resistance, and stemness. Single-cell and bulk expression profiling revealed their similarity to primary ALL cells isolated from pediatric and adult patients at minimal residual disease (MRD). Therapeutically adverse characteristics were reversible, as resistant, dormant cells became sensitive to treatment and started proliferating when dissociated from the in vivo environment. Our data suggest that ALL patients might profit from therapeutic strategies that release MRD cells from the niche. Overall design: Gene expression profiles from two PDX ALL Samples (ALL-199 & ALL-265) were generated for either dormant (LRC) vs. dividing (non-LRC) cells or drug treated vs. non-treated cells. For single cell analysis one mouse were analyzed for each condition.
Publication Title
Characterization of Rare, Dormant, and Therapy-Resistant Cells in Acute Lymphoblastic Leukemia.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
Most hepatocellular carcinomas in younger patients from Peru arise from non-cirrhotic livers. Histological examination of the non-tumor liver tissues highlights the presence of clear cell foci in a significant fraction of Peruvian patients with hepatocellular carcinoma.
Publication Title
Liver clear cell foci and viral infection are associated with non-cirrhotic, non-fibrolamellar hepatocellular carcinoma in young patients from South America.
Sample Metadata Fields
Specimen part, Disease stage, Subject
View Samples- Mus musculus
- 11 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Hexose-6-phosphate dehydrogenase (H6PD)is the initial component of a pentose phosphate pathway inside the endoplasmic reticulum (ER) that generates NADPH for ER enzymes. In liver, H6PD is required for the 11-oxoreductase activity of 11ss-hydroxysteroid dehydrogenase type 1 (11ss-HSD1), which converts inactive 11-oxo glucocorticoids to their active 11-hydroxyl counterparts; consequently, H6PD null mice are relatively insensitive to glucocorticoids, exhibiting fasting hypoglycemia, increased insulin sensitivity despite elevated circulating levels of corticosterone, and increased basal and insulin-stimulated glucose uptake in muscles normally enriched in Type II (fast) fibers which have increased glycogen content. They also display a progressive vacuolar myopathy evident after 4 weeks of age.
Publication Title
Deletion of hexose-6-phosphate dehydrogenase activates the unfolded protein response pathway and induces skeletal myopathy.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 53 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Study the training exercise effects in chronic obstructive pulmonary disease (COPD) patients and aged-matched healthy individuals. Skeletal muscle biopsies from 9 stable COPD patients with normal fat free mass index (FFMI, 21Kg/m2) (COPDN), 6 COPD patients with low FFMI (16Kg/m2) (COPL), and 12 healthy sedentary subjects (FFMI 21Kg/m2) before and after 8 weeks of a supervised endurance exercise program were analyzed.
Publication Title
A systems biology approach identifies molecular networks defining skeletal muscle abnormalities in chronic obstructive pulmonary disease.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Subject
View Samples- Homo sapiens
- 98 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Despite widespread use of sunscreens that minimize erythema by blocking ultraviolet B (UVB) radiation, incidence rates of melanoma continue to rise. In considering this disparity between intervention and disease prevalence, we investigated the in vivo transcriptome of human skin treated with sunscreen and solar-simulated radiation (ssR). A focal skin area of healthy participants was exposed to ssR at 1 minimal erythema dose (MED), 0.1 MED or 100 J/m2 with or without prior application of sunscreen, or to non-UVB-spectrum of ssR (solar-simulated UVA/visible/infrared radiation: ssA). Skin biopsies were analyzed using expression microarrays.
Publication Title
Transcriptional signatures of full-spectrum and non-UVB-spectrum solar irradiation in human skin.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 14 Downloadable Samples
- IlluminaHiSeq2000
Description
High expression of the ETS family transcription factor ERG is associated with poor clinical outcome in acute myeloid leukemia (AML) and acute T-cell lymphoblastic leukemia (T-ALL). In murine models, high ERG expression induces both T-ALL and AML. However, no study to date has defined the effect of high ERG expression on primary human hematopoietic cells. In the present study, human CD34+ cells were transduced with retroviral vectors to elevate ERG gene expression to levels detected in high ERG AML. RNA sequencing was performed on purified populations of transduced cells to define the effects of high ERG on gene expression in human CD34+ cells. Integration of the genome-wide expression data with other data sets revealed that high ERG drives an expression signature that shares features of normal hematopoietic stem cells, high ERG AMLs, early T-cell precursor-ALLs and leukemic stem cell signatures associated with poor clinical outcome. Functional assays linked this gene expression profile to enhanced progenitor cell expansion. These results support a model whereby a stem cell gene expression network driven by high ERG in human cells enhances the expansion of the progenitor pool, providing opportunity for the acquisition and propagation of mutations and the development of leukemia. Overall design: RNA sequencing in ERG overexpressing human CD34+ cells
Publication Title
Overexpression of ERG in cord blood progenitors promotes expansion and recapitulates molecular signatures of high ERG leukemias.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Efferent inhibition of cochlear outer hair cells is mediated by nicotinic cholinergic receptors containing alpha9 (a9) and alpha10 subunits. Mice lacking a9 nicotinic subunits fail to exhibit classic olivocochlear responses and are characterized by abnormal synaptic morphology at the base of outer hair cells. To detail molecular changes induced upon the loss of a9 subunit, we sampled cochlear RNA from wild type and a9 null mice at postnatal (P) days spanning periods of synapse formation and maturation (P3, P7, P13 and P60). Our findings point to a delay in cochlear maturation starting at the onset of hearing (P13), as well as an up-regulation of various GABA receptor subunits in adult mice lacking the a9 nicotinic subunit.
Publication Title
Lack of nAChR activity depresses cochlear maturation and up-regulates GABA system components: temporal profiling of gene expression in alpha9 null mice.
Sample Metadata Fields
Specimen part
View Samples