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GSE87317
Mus musculus
10 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
BACKGROUND & AIMS: Inflammatory Bowel Disease (IBD) is a chronic inflammatory condition driven by loss of homeostasis between the mucosal immune system, the commensal gut microbiota, and the intestinal epithelium. Our overarching goal is to understand how these components of the intestinal ecosystem cooperate to control homeostasis and to identify novel signal transduction pathways that become dysregulated in IBD. METHODS: We have applied a multi-scale systems biology approach to a mouse model of chronic colitis. We combined quantitative measures of epithelial hyperplasia and immune infiltration with multivariate analysis of inter- and intra-cellular signaling molecules in order to generate a tissue level model of the inflamed disease state. We utilized the computational model to identify signaling pathways that were dysregulated in the context of colitis and then validated model predictions by measuring the effect of small molecule pathway inhibitors on colitis. RESULTS: Our data-driven computational model identified mTOR signaling as a potential driver of inflammation and mTOR inhibition reversed the molecular, immunological, and epithelial manifestations of colitis. Inhibition of Notch signaling, which induces epithelial differentiation, had the same effect, suggesting that the epithelial proliferation/differentiation state plays a key role in maintaining homeostasis of the colon. Confirming this, we found that colonic organoids grown ex vivo showed a similar relationship between proliferation and cytokine expression, even in the absence of gut bacteria and immune cells. CONCLUSIONS: Our study provides a tissue-level systems biology perspective of murine colitis and suggests that mTOR plays a key role in regulating colonic homeostasis by controlling epithelial proliferation/differentiation state.
Publication Title
The colonic epithelium plays an active role in promoting colitis by shaping the tissue cytokine profile.
Sample Metadata Fields
Specimen part
View Samples- Rattus norvegicus
- 20 Downloadable Samples
- Affymetrix Rat Gene 1.1 ST Array (ragene11st)
Description
Identify differentially expressed genes related to the neurodegenerative process in a new animal model of hepatic encephalopathy (HE).
Publication Title
Cerebellar neurodegeneration in a new rat model of episodic hepatic encephalopathy.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 16 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Cyclin D3 is critical hematopoiesis and loss of cyclin D3 leads to resistance to transformation of bone marrow progenitors by Notch1-IC.
Publication Title
Therapeutic targeting of the cyclin D3:CDK4/6 complex in T cell leukemia.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 14 Downloadable Samples
NextSeq 500
Description
Diamond-Blackfan anemia (DBA) is a rare bone marrow failure disorder that affects 7 out of 1,000,000 live births and has been associated with mutations in components of the ribosome. In order to characterize the genetic landscape of this heterogeneous disorder, we recruited a cohort of 472 individuals with a clinical diagnosis of DBA and performed whole exome sequencing (WES). We identified rare and predicted damaging mutations in likely causal genes for 78% of individuals. The majority of mutations were singletons, absent from population databases, predicted to cause loss of function, and in one of 19 previously reported ribosomal protein (RP) encoding genes. Using exon coverage estimates, we identified and validated 31 deletions in RP genes. We also observed an enrichment for extended splice site mutations and validated their diverse effects using RNA sequencing in individual-derived cell lines. Leveraging the size of our cohort, we observed robust genotype-phenotype associations with congenital abnormalities and treatment outcomes. We further identified rare mutations in 7 previously unreported RP genes that may cause DBA, as well as several distinct disorders that appear to phenocopy DBA, including 9 individuals with biallelic CECR1 mutations that result in deficiency of ADA2. However, no new genes were identified at exome-wide significance, suggesting that there are no unidentified genes containing mutations readily identified by WES that explain > 5% of DBA cases. Overall, this report should not only inform clinical practice for DBA individuals, but also the design and analysis of rare variant studies for heterogeneous Mendelian disorders. Overall design: 9 individuals with DBA with putative splice mutations and 5 control individuals were processed for RNA-seq.
Publication Title
The Genetic Landscape of Diamond-Blackfan Anemia.
Sample Metadata Fields
Specimen part, Disease, Subject
View Samples- Mus musculus
- 9 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Activated NOTCH1 induces T-ALL in mice when transduced in bone marrow (BM) cells. T-ALL cells activate the calcineurin/NFAT pathway in vivo (Medyouf H. et al. Nat Med 2007 [PMID 17515895]).
Publication Title
Leukemia-initiating cell activity requires calcineurin in T-cell acute lymphoblastic leukemia.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 229 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
One of our new major finding among the genes that contributes to MS susceptibility is ICSBP1. The so called disease modifying therapies like interferon-beta (IFN-), possibly acting on the peripheral T-cells, reduce the disease activity and the clinical progression, with a MRI-detectable effect in preventing lesion burden and cerebral atrophy development in RR-MS. It suggests a critical role of peripheral blood mononuclear cells (PBMCs) immune response and modulation in developing inflammation in the brain. We tested the hypothesis that the genetic effect of the susceptible allele ICSBP1 can impact the gene expression profile of molecules belonging to the interferon pathway. We therefore interrogated the PBMC for changes in gene expression profile. We correlate those changes with the minor allele frequency for ICSBP1, performing independent quantitative trait analysis for each treatment category. Expression Quantitative Trait Loci Association with a p value < 0.05 have been used in follow up analysis. The regression coefficient of the Quantitative trait association represents the degree of correlation between the gene expression for each interrogated target gene and the minor allele frequency of the SNP for our gene of interest. This coefficient has been used as input in the subsequent Gene Set Enrichment Analysis performed in a pre-ranked approach. The resulting GSEA-SNP method rests on the assumption that SNPs underlying a disease phenotype might affect genes constituting a signaling pathway or genes with a common regulation. Therefore, GSEA-SNP can facilitate the identification of pathways or of underlying biological mechanisms.
Publication Title
Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 15 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
The unfolded protein response (UPR) maintains endoplasmic reticulum (ER) proteostasis through the activation of transcription factors such as XBP1s and ATF6. The functional consequences of these transcription factors for ER proteostasis remain poorly defined. Here, we describe methodology that enables orthogonal, small molecule-mediated activation of the UPR-associated transcription factors XBP1s and/or ATF6 in the same cell independent of stress. We employ transcriptomics and quantitative proteomics to evaluate ER proteostasis network remodeling owing to the XBP1s and/or ATF6 transcriptional programs. Furthermore, we demonstrate that the three ER proteostasis environments accessible by activating XBP1s and/or ATF6 differentially influence the folding, trafficking, and degradation of destabilized ER client proteins without globally affecting the endogenous proteome. Our data reveal how the ER proteostasis network is remodeled by the XBP1s and/or ATF6 transcriptional programs at the molecular level and demonstrate the potential for selectively restoring aberrant ER proteostasis of pathologic, destabilized proteins through arm-selective UPR-activation.
Publication Title
Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
The unfolded protein response (UPR) maintains endoplasmic reticulum (ER) proteostasis through the activation of transcription factors such as XBP1s and ATF6. The functional consequences of these transcription factors for ER proteostasis remain poorly defined. Here, we describe methodology that enables orthogonal, small molecule-mediated activation of the UPR-associated transcription factors XBP1s and/or ATF6 in the same cell independent of stress. We employ transcriptomics and quantitative proteomics to evaluate ER proteostasis network remodeling owing to the XBP1s and/or ATF6 transcriptional programs. Furthermore, we demonstrate that the three ER proteostasis environments accessible by activating XBP1s and/or ATF6 differentially influence the folding, trafficking, and degradation of destabilized ER client proteins without globally affecting the endogenous proteome. Our data reveal how the ER proteostasis network is remodeled by the XBP1s and/or ATF6 transcriptional programs at the molecular level and demonstrate the potential for selectively restoring aberrant ER proteostasis of pathologic, destabilized proteins through arm-selective UPR-activation.
Publication Title
Stress-independent activation of XBP1s and/or ATF6 reveals three functionally diverse ER proteostasis environments.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 33 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Molecular Aging of Human Liver: An Epigenetic/Transcriptomic Signature.
Sample Metadata Fields
Sex, Age, Specimen part, Disease
View Samples