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SRP058856
Homo sapiens
88 Downloadable Samples
IlluminaHiSeq2000
Description
Small molecule inhibitors of the bromodomain and extraterminal (BET) family of proteins are in clinical trials for a variety of cancers, but patient selection strategies are limited. This is due in part to the heterogeneity of response following BET inhibition (BETi), which includes differentiation, senescence, and cell death in subsets of cancer cell lines. To elucidate the dominant features defining response to BETi, we carried out phenotypic and gene expression analysis of both treatment naïve cell lines and engineered tolerant lines. We found that both de novo and acquired tolerance to BET inhibition are driven by the robustness of the apoptotic response and that genetic or pharmacological manipulation of the apoptotic signaling network can modify the phenotypic response to BETi. We further identify that ordered expression of the apoptotic genes BCL2, BCL2L1, and BAD significantly predicts response to BETi. Our findings highlight the role of the apoptotic network in response to BETi, providing a molecular basis for patient stratification and combination therapies. Overall design: Gene expression profiling of A375 melanoma cells or NOMO-1 AML cells treated with DMSO or the BET inhibitor, CPI203. Also, gene expression profiling of the respective derived BETi-tolerant cells treated with DMSO or CPI203.
Publication Title
Preclinical Anticancer Efficacy of BET Bromodomain Inhibitors Is Determined by the Apoptotic Response.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 28 Downloadable Samples
- IlluminaHiSeq2000
Description
Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Phenotypic effects are preceded by the direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4 and the subsequent down-regulation of the IRF4 transcriptional program. Ectopic expression of IRF4 antagonizes the phenotypic effects of CBP/EP300 bromodomain inhibition and prevents the suppression of the IRF4 target c-MYC. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network. Overall design: Through the use of CBP/EP300 bromodomain inhibitors (CBP/EP300i), we demonstrate that MYC expression in BETi-resistant cells is dependent on CBP/EP300 bromodomains and that treatment with CBP/EP300i restores phenotypic sensitivity.
Publication Title
Bromodomain inhibition of the transcriptional coactivators CBP/EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 24 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Renal excretion of water and major electrolytes exhibits a significant circadian rhythm. This functional periodicity is believed to result, at least in part, from circadian changes in secretion/reabsorption capacities of the distal nephron and collecting ducts. Here, we studied the molecular mechanisms underlying circadian rhythms in the distal nephron segments, i.e. distal convoluted tubule (DCT) and connecting tubule (CNT) and, the cortical collecting duct (CCD). Temporal expression analysis performed on microdissected mouse DCT/CNT or CCD revealed a marked circadian rhythmicity in the expression of a large number of genes crucially involved in various homeostatic functions of the kidney. This analysis also revealed that both DCT/CNT and CCD possess an intrinsic circadian timing system characterized by robust oscillations in the expression of circadian core clock genes (clock, bma11, npas2, per, cry, nr1d1) and clock-controlled Par bZip transcriptional factors dbp, hlf and tef. The clock knockout mice or mice devoid of dbp/hlf/tef (triple knockout) exhibit significant changes in renal expression of several key regulators of water or sodium balance (vasopressin V2 receptor, aquaporin-2, aquaporin-4, alphaENaC). Functionally, the loss of clock leads to a complex phenotype characterized by partial diabetes insipidus, dysregulation of sodium excretion rhythms and a significant decrease in blood pressure. Collectively, this study uncovers a major role of molecular clock in renal function.
Publication Title
Molecular clock is involved in predictive circadian adjustment of renal function.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 67 Downloadable Samples
- Illumina HiSeq 2000
Description
RNA-seq libraries purified from the visual cortices of neurons expressing Emx-, GAD2-, PV-, SST-, or VIP-Cre using the Ribotag allele. Seq libraries are provided from mice raised in standard housing, or housed in the dark for two weeks (dark-housed), or dark-housed and then exposed to light for 1, 3, or 7.5 hours. These seq libraries represent the genetic response of distinct types of cortical interneurons to altered sensory experience. Overall design: To explore how sensory experience affects gene expression, we examined this process in the visual cortex of adult mice that were housed in standard conditions, in complete darkness (i.e. dark-housed), or dark-housed and then exposed to light for increasing amounts of time. We generated mice that were heterozygous for alleles of either Emx-,Gad2-,Sst-,Vip- or Pv-Cre, and were also heterozygous for the Rpl22-HA (RiboTag) allele, which expresses an HA-tagged ribosomal protein specifically in Cre-expressing neurons. We performed RNA-Seq on RNA isolated from the dark-housed/light-exposed RiboTag-mice; Experiments were done in 3 biological replicates and the visual cortices of 3 mice were pooled per sample at each time-point and for each Cre line.
Publication Title
Sensory experience regulates cortical inhibition by inducing IGF1 in VIP neurons.
Sample Metadata Fields
Age, Specimen part, Cell line, Subject
View Samples- Mus musculus
- 12 Downloadable Samples
- Illumina HiSeq 2500, Illumina HiSeq 2000
Description
The circadian clock controls a wide variety of metabolic and homeostatic processes in a number of tissues, including the kidney. However, the role of the renal circadian clocks remains largely unknown. To address this question we performed transcriptomic analysis in mice with inducible and conditional ablation of the circadian clock system in the renal tubular cells (Bmal1lox/lox/Pax8-rtTA/LC1 mice). Deep sequencing of the renal transcriptome revealed significant changes in the expression of genes related to metabolic pathways and organic anion transport. In parallel, kidneys from Bmal1lox/lox/Pax8-rtTA/LC1 mice exhibited a significant decrease in the NAD+/NADH ratio suggesting an increased anaerobic glycolysis and/or decreased mitochondrial function. In-depth analysis of two selected pathways revealed (i) a significant increase in plasma urea levels correlating with increased renal arginase 2 (Arg2) activity, hyperargininemia and increase of the kidney arginine content; (ii) a significantly increased plasma creatinine concentration and reduced capacity of the kidney to secrete anionic drugs (furosemide), paralleled by a ~80% decrease in the expression levels of organic anion transporter OAT3 (SLC22a8). Collectively, these results indicate that the renal circadian clocks control a variety of metabolic/homeostatic processes at both the intra-renal and systemic levels and are involved in drug disposition. Overall design: Mice with a specific ablation of the Arntl gene encoding BMAL1 in the renal tubular cells were compared to wild-type littermate at ZT4 and ZT16 (ZT – Zeitgeber time units; ZT0 is the time of light on and ZT12 is the time of light off).
Publication Title
Nephron-Specific Deletion of Circadian Clock Gene Bmal1 Alters the Plasma and Renal Metabolome and Impairs Drug Disposition.
Sample Metadata Fields
Specimen part, Subject, Time
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
NPY signalling via osteoblastic Y1 receptors has been shown to control bone mass but also contributes significantly to the control of whole-body insulin secretion and glucose homeostasis in mice through the release of novel factor(s) which are different from the previously implicated osteocalcin.
Publication Title
Osteoglycin, a novel coordinator of bone and glucose homeostasis.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 39 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Identify biomarkers to predict response to therapy in polyarticular juvenile idiopathic arthritis (JIA) using gene expression microarrays.
Publication Title
The meaning of clinical remission in polyarticular juvenile idiopathic arthritis: gene expression profiling in peripheral blood mononuclear cells identifies distinct disease states.
Sample Metadata Fields
Specimen part, Disease, Disease stage
View Samples- Homo sapiens
- 288 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
A major goal of systems biology is the development of models that accurately predict responses to perturbation. Constructing such models requires the collection of dense measurements of system states, yet transformation of data into predictive constructs remains a challenge. To begin to model human immunity, we analyzed immune parameters in depth both at baseline and in response to influenza vaccination.
Publication Title
Global analyses of human immune variation reveal baseline predictors of postvaccination responses.
Sample Metadata Fields
Sex, Age, Specimen part, Subject
View Samples- Mus musculus
- 29 Downloadable Samples
- Illumina HiSeq 2000
Description
The ability to form memories is a prerequisite for an organism’s behavioural adaptation to environmental changes. At the molecular level, the acquisition and maintenance of memory requires changes in chromatin modifications. In an effort to unravel the epigenetic network underlying both short- and long-term memory, we examined chromatin modification changes in two distinct mouse brain regions, two cell-types, and three time-points before and after contextual learning. Here we show that histone modifications predominantly change during memory acquisition and correlate surprisingly little with changes in gene expression. While long-lasting changes are almost exclusive to neurons, learning-related histone modification and DNA methylation changes occur also in non-neuronal cell types, suggesting a functional role for non-neuronal cells in epigenetic learning. Finally, our data provides evidence for a molecular framework of memory acquisition and maintenance, wherein DNA methylation could alter the expression and splicing of genes involved in functional plasticity and synaptic wiring. Overall design: We examined chromatin modification changes in two distinct mouse brain regions (CA1 and ACC), two cell-types (neurons, non-neurons), and three time-points before and after contextual learning (naive, 1h, 4w).
Publication Title
DNA methylation changes in plasticity genes accompany the formation and maintenance of memory.
Sample Metadata Fields
Sex, Age, Cell line, Subject
View Samples- Mus musculus
- 33 Downloadable Samples
- Illumina HiSeq 2000
Description
Innate immune memory is a vital mechanism of myeloid cell plasticity that occurs in response to environmental stimuli and alters subsequent immune responses. Two types of immunological imprinting can be distinguished—training and tolerance. These are epigenetically mediated and enhance or suppress subsequent inflammation, respectively. Whether immune memory occurs in tissue-resident macrophages in vivo and how it may affect pathology remains largely unknown. Here we demonstrate that peripherally applied inflammatory stimuli induce acute immune training and tolerance in the brain and lead to differential epigenetic reprogramming of brain-resident macrophages (microglia) that persists for at least six months. Strikingly, in a mouse model of Alzheimer's pathology, immune training exacerbates cerebral beta-amyloidosis and immune tolerance alleviates it; similarly, peripheral immune stimulation modifies pathological features after stroke. Our results identify immune memory in the brain as an important modifier of neuropathology. Overall design: mRNA was isolated from FACS-purified microglia and prepared for RNA-sequencing.
Publication Title
Innate immune memory in the brain shapes neurological disease hallmarks.
Sample Metadata Fields
Sex, Specimen part, Treatment, Subject
View Samples