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GSE4648
Mus musculus
198 Downloadable Samples
Affymetrix Murine Genome U74A Version 2 Array (mgu74av2)
Description
We report a genome-wide survey of early responses of the mouse heart transcriptome to acute myocardial infarction (AMI). For three regions of the left ventricle (LV), namely ischemic/infarcted tissue (IF), the surviving LV free wall (FW) and the interventricular septum (IVS), 36,899 transcripts were assayed at six time points from 15 min to 48 h post-AMI in both AMI and sham surgery mice. For each transcript, temporal expression patterns were systematically compared between AMI and sham groups, which identified 515 AMI-responsive genes in IF tissue, 35 in the FW, 7 in the IVS, with three genes induced in all three regions. Using the literature, we assigned functional annotations to all 519 nonredundant AMI-induced genes and present two testable models for central signaling pathways induced early post-AMI. First, the early induction of 15 genes involved in assembly and activation of the activator protein-1 (AP-1) family of transcription factors implicates AP-1 as a dominant regulator of earliest post-ischemic molecular events. Second, dramatic increases in transcripts for arginase 1 (ARG1), the enzymes of polyamine biosynthesis and protein inhibitor of nitric oxide synthase (NOS) activity indicates that NO production may be regulated, in part, by inhibition of NOS and coordinate depletion of the NOS substrate, L-arginine. ARG1 was the single most highly induced transcript in the database (121-fold in IF region) and its induction in heart has not been previously reported.
Publication Title
Earliest changes in the left ventricular transcriptome postmyocardial infarction.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 31 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Integration Analysis of Three Omics Data Using Penalized Regression Methods: An Application to Bladder Cancer.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 31 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Omics data integration is becoming necessary to investigate the still unknown genomic mechanisms of complex diseases. During the integration process, many challenges arise such as data heterogeneity, the smaller number of individuals in comparison to the number of parameters, multicollinearity, and interpretation and validation of results due to their complexity and lack of knowledge about biological mechanisms. To overcome some of these issues, innovative statistical approaches are being developed. In this work, we applied penalized regression methods (LASSO and ENET) to explore relationships between common genetic variants, DNA methylation and gene expression measured in bladder tumor samples and have proposed a permutation-based method to concomitantly assess significance and correct by multiple testing with the MaxT algorithm. The overall analysis flow consisted of three steps: (1) SNPs/CpGs were selected per each gene probe within 1Mb window upstream and downstream the gene; (2) LASSO and ENET were applied to assess the association between each expression probe and the selected SNPs/CpGs in three multivariable models (SNP, CPG, and Global models, the latter integrating SNPs and CPGs); and (3) the significance of each model was assessed using the permutation-based MaxT method. We identified 48 genes whom expression levels were associated with both SNPs and GPGs. Importantly, we replicated results for 36 (75%) of them in an independent data set (TCGA). We checked the performance of the proposed method with a simulation study and further supported our results with a biological interpretation based on an enrichment analysis. The approach we propose allows reducing computational time and is flexibly and easy to implement when analyzing several omics data. Our results highlight the importance of integrating omics data by applying appropriate statistical strategies to discover new insights into the complexity of disease genetic mechanisms.
Publication Title
Integration Analysis of Three Omics Data Using Penalized Regression Methods: An Application to Bladder Cancer.
Sample Metadata Fields
Specimen part
View Samples- Drosophila melanogaster
- 16 Downloadable Samples
- Affymetrix Drosophila Genome 2.0 Array (drosophila2)
Description
Age-dependent electrical and morphological remodeling of the Drosophila heart caused by hERG/seizure mutations
Publication Title
Age-dependent electrical and morphological remodeling of the Drosophila heart caused by hERG/seizure mutations.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 15 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Translocations of ETS transcription factors are driver mutations in diverse cancers. We investigated the genomic network of the ETS fusion EWS/FLI1 in Ewing's sarcoma (ESFT) as a model of ETS-driven tumorigenesis. ChIP-Seq and transcriptional analysis identified E2F3 as a principle co-factor of EWSFLI1 defining functionally distinct gene sets. While EWS/FLI1 binding independent of E2F3 predominantly associated with repressed differentiation genes, significant co-localization with E2F3 was discovered at proximal promoters of activated growth-related genes. Thus, EWS/FLI1 promotes oncogenesis by simultaneously perturbing differentiation state and augmenting the expression of genes co-regulated by E2F3. Integration of additional E2F3 and ERG localization data from prostate cancer containing TMPRSS2/ERG verified that the ETS-E2F module is also found in prostate cancer and may be of general relevance to ETS driven cancers.
Publication Title
Oncogenic ETS fusions deregulate E2F3 target genes in Ewing sarcoma and prostate cancer.
Sample Metadata Fields
Disease, Cell line, Treatment, Time
View Samples- Homo sapiens
- 10 Downloadable Samples
IlluminaHiSeq1500
Description
About 50% of human malignancies exhibit unregulated signalling through the Ras-ERK1/2 (ERK) pathway, as a consequence of activating mutations in members of Ras and Raf families. However, the quest for alternative Ras-ERK pathway-directed therapies is desirable. Upon phosphorylation ERK dimerize. We had previously demonstrated that dimerization is essential for ERK extranuclear but not nuclear signaling. Furthermore, by molecular biology approaches, we showed that specifically inhibiting ERK extranuclear component, by impeding ERK dimerization, is sufficient for curtailing tumor progression. Here, we have identified a small molecule inhibitor for ERK dimerization in vitro and in vivo that, without affecting ERK phosphorylation, prevents tumorigenesis driven by Ras-ERK pathway oncogenes, both in cellular and animal models. Importantly, this compound is unaffected by resistance-acquisition processes that hamper “classical” Ras-ERK pathway inhibitors. Thus, ERK dimerization inhibitors provide the proof of principle for two novel concepts in cancer therapy: 1) The blockade of sublocalization-specific sub-signals, rather than total signals, as a means of effectively counteracting oncogenic Ras-ERK signaling. 2) Targeting regulatory protein-protein interactions such as dimerization, rather than catalytic activities, within a signaling route, as an approach for producing effective anti-tumoral agents. Strategies aimed at preventing aberrant flux through this route remain an attractive option for therapeutic intervention in cancer. In this respect, drugs inhibiting the kinase activities of BRaf and MEK have yielded promising results. Overall design: A375p cells treated with10 µM of either DEL22379, SCH772984 or DMSO as a control for two hours. mRNA from A375p cells was extrated using RNeasy mini kit (Qiagen, Germany) according to the manufacturer''s instructions. Cells were previously treated with10 µM of either DEL22379, SCH772984 or DMSO as a control for two hours.
Publication Title
Small Molecule Inhibition of ERK Dimerization Prevents Tumorigenesis by RAS-ERK Pathway Oncogenes.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 68 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This series represents bone marrow aspirates from smoldering multiple myeloma patients
Publication Title
Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 48 Downloadable Samples
- NextSeq 500
Description
Liver X Receptors (LXRa and ß) are ligand-activated transcription factors that play a key role in the control of lipid homeostasis, as well as modulation of immunity and inflammation. Besides ligand binding, LXR activity can be regulated by posttranslational modifications, such as phosphorylation. This study aims to assess changes in bone marrow derived macrophage transcriptional profiles of mice that carry LysMcre directed phosphorylation deficient-version of LXRa compared (S196A) to wild-type (WT). Overall design: BMDM mRNA profiles of either LdlrKO or M-LXRa-S196A-LdlrKO male mice after being fed a Western diet for 12 weeks. 12 samples, 4 groups, in triplicate: (1) LdlrKO basal, (2) LdlrKO+ ligand, (3) M-LXRa-S196A-LdlrKO basal, (4) M-LXRa-S196A-LdlrKO+ligand
Publication Title
Disrupting LXRα phosphorylation promotes FoxM1 expression and modulates atherosclerosis by inducing macrophage proliferation.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2000
Description
Purpose:The goals of this study was to determine alterations in expression levels of transcripts downstream of a dominant-negative transcription factor. Quantitative reverse transcription polymerase chain reaction (qRT–PCR) methods was used to confirm the altered expression of targets. Methods: Striatal mRNA profiles of 11-month-old wild-type (WT) and Nestin-Cre X PPAR delta E411P mice were generated by deep sequencing, in triplicate, using Illumina HiSeq 2000. The sequence reads that passed quality filters were analyzed at the transcript isoform level with TopHat followed by Cufflinks. qRT–PCR validation was performed using TaqMan and SYBR Green assays. Western blots, and immunofluorescence was also used to confirm if altered mRNA levels translated to changes at the protein level. Results: Using data analysis workflow, we mapped sequence reads for each sample to the mouse genome (build mm9) and identified transcripts in the striatum of WT and PPARdelta E411P mice. Conclusions: Our study found multiple transcripts altered in the striatum of the Nestin-Cre x PPAR delta E411P mice as compared to WT striatum, as generated by RNA-SEQ in biologic replicates. Overall design: Striatal mRNA profiles of 11-month-old wild type (WT) and Nestin-Cre X PPAR delta E411P mice were generated by deep sequencing, in triplicate, using Illumina HiSeq2000.
Publication Title
PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 11 Downloadable Samples
- Affymetrix Mouse Expression 430A Array (moe430a)
Description
BACKGROUND: Hox genes are implicated in hematopoietic stem cell (HSC) regulation as well as in leukemia development through translocation with the nucleoporin gene NUP98. Interestingly, an engineered NUP98-HOXA10 (NA10) fusion can induce a several hundred-fold expansion of HSCs in vitro and NA10 and the AML-associated fusion gene NUP98-HOXD13 (ND13) have a virtually indistinguishable ability to transform myeloid progenitor cells in vitro and to induce leukemia in collaboration with MEIS1 in vivo. METHODOLOGY/PRINCIPAL FINDINGS: These findings provided a potentially powerful approach to identify key pathways mediating Hox-induced expansion and transformation of HSCs by identifying gene expression changes commonly induced by ND13 and NA10 but not by a NUP98-Hox fusion with a non-DNA binding homedomain mutation (N51S). The gene expression repertoire of purified murine bone marrow Sca-1+Lin- cells transduced with retroviral vectors encoding for these genes was established using the Affymetrix GeneChip MOE430A. Approximately seventy genes were differentially expressed in ND13 and NA10 cells that were significantly changed by both compared to the ND13(N51S) mutant. Intriguingly, several of these potential Hox target genes have been implicated in HSC expansion and self-renewal, including the tyrosine kinase receptor Flt3, the prion protein, Prnp, hepatic leukemia factor, Hlf and Jagged-2, Jag2. CONCLUSIONS: In conclusion this study has identified several novel Hox downstream target genes and provides important new leads to key regulators of the expansion and transformation of hematopoietic stem cells by Hox.
Publication Title
Candidate genes for expansion and transformation of hematopoietic stem cells by NUP98-HOX fusion genes.
Sample Metadata Fields
No sample metadata fields
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