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GSE62846
Mus musculus
12 Downloadable Samples
Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Strategies to enhance islet b-cell survival and regeneration while refraining inflammation through manipulation of molecular targets would provide means to stably replenish the deteriorating functional b-cell mass detected in both Type 1 and Type 2 Diabetes Mellitus (T1DM and T2DM). Herein we report that over expression of the islet enriched transcription factor Pax4 refrains development of hyperglycemia in the RIP-B7.1 mouse model of T1DM through reduced insulitis, decreased b-cell apoptosis correlating with diminished DNA damage and increased proliferation. Transcriptomics revealed up regulation of genes involved in immunomodulation, cell cycle and ER homeostasis in islets over expressing Pax4 as compared to the T2DM-linked mutant variant Pax4R129W. Pax4 but not Pax4R129W protected islets from thapsigargin-mediated ER-stress apoptosis. Collectively, Pax4 is a critical signaling hub coordinating regulation of distinct molecular pathways resulting in improved b-cell fitness whereas Pax4R129W sensitizes to death under stress. More importantly we highlight potential common pharmacological targets for the treatment of DM.
Publication Title
PAX4 preserves endoplasmic reticulum integrity preventing beta cell degeneration in a mouse model of type 1 diabetes mellitus.
Sample Metadata Fields
Age, Specimen part, Treatment
View Samples- Homo sapiens
- 437 Downloadable Samples
Illumina HiSeq 4000
Description
Background: Single-cell RNA-Seq can be a valuable and unbiased tool to dissect cellular heterogeneity, despite the transcriptome’s limitations in describing higher functional phenotypes and protein events. Perhaps the most important shortfall with transcriptomic ‘snapshots’ of cell populations is that they risk being descriptive, only cataloging heterogeneity at one point in time, and without microenvironmental context. Studying the genetic (‘nature’) and environmental (‘nurture’) modifiers of heterogeneity, and how cell population dynamics unfold over time in response to these modifiers is key when studying highly plastic cells such as macrophages. Results: We introduce the programmable PolarisTM microfluidic lab-on-chip for single-cell sequencing, which performs live-cell imaging while controlling for the culture microenvironment of each cell. Using gene-edited macrophages we demonstrate how previously unappreciated knockout effects of SAMHD1, such as an altered oxidative stress response, have a large paracrine signaling component. Furthermore, we demonstrate single-cell pathway enrichments for cell cycle arrest and APOBEC3G degradation, both associated with the oxidative stress response and altered proteostasis. Interestingly, SAMHD1 and APOBEC3 are both HIV-1 inhibitors (‘restriction factors’), with no previously known co-regulation. Conclusion: As single-cell methods continue to mature, so will the ability to move beyond simple ‘snapshots’ of cell populations towards studying the determinants of population dynamics. By combining single-cell culture, live-cell imaging, and single-cell sequencing, we have demonstrated the ability to study cell phenotypes and microenvironmental influences. It’s these microenvironmental components - ignored by standard single-cell workflows - that likely determine how macrophages, for example, react to inflammation and form treatment resistant HIV reservoirs. Overall design: Stem cell derived macrophages (wildtype and SAMHD1 knockout) were single-cell cultured for 1h or 8h under for different media conditions (with/without lipopolysaccharide, with/without conditioned media to account for inter-macrophage signalling)
Publication Title
The nature and nurture of cell heterogeneity: accounting for macrophage gene-environment interactions with single-cell RNA-Seq.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Docetaxel-based chemotherapy is the standard first-line therapy in metastatic castration-resistant prostate cancer. However, most patients eventually develop resistance to this treatment.
Publication Title
Identification of docetaxel resistance genes in castration-resistant prostate cancer.
Sample Metadata Fields
Disease, Disease stage, Cell line, Treatment
View Samples- Homo sapiens
- 189 Downloadable Samples
Description
Intestinal health is sustained by cooperation between diverse cell types, including epithelial cells, immune cells and stromal cells. Colonic stromal cells provide critical structural support but also regulate mucosal immunity, tolerance and inflammatory responses. Although mucosal stromal cells display substantial variability and plasticity, a paucity of unique genetic markers has precluded the identification of distinct stromal populations and functions. We used single-cell RNA-sequencing to uncover heterogeneity and subtype-specific markers of individual colonic stromal cells in health and ulcerative colitis (UC). Marker-free transcriptional clustering revealed four distinct stromal populations in healthy colon, corresponding to myofibroblasts and three previously unknown distinct subsets of fibroblasts. These fibroblast subsets were substantially remodeled in UC compared to healthy colon: inflamed UC colon was depleted for a healthy fibroblast subpopulation associated with epithelial cell homeostasis, and enriched for a novel disease-associated subtype expressing pro-inflammatory genes. Thus, we have discovered new, molecularly distinct colonic stromal cell subtypes that are altered in human disease. Overall design: Colonic lamina propria mesenchymal cells from 3 healthy donors. 183 single cell libraries, 6 bulk controls, 3 empty well controls. Individual donors processed as separate batches with Fluidigm C1 IFCs and pooled for sequencing (2 x Illumina HiSeq 2500 lanes).
Publication Title
Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 162 Downloadable Samples
- Illumina HiSeq 4000
Description
Intestinal health is sustained by cooperation between diverse cell types, including epithelial cells, immune cells and stromal cells. Colonic stromal cells provide critical structural support but also regulate mucosal immunity, tolerance and inflammatory responses. Although mucosal stromal cells display substantial variability and plasticity, a paucity of unique genetic markers has precluded the identification of distinct stromal populations and functions. We used single-cell RNA-sequencing to uncover heterogeneity and subtype-specific markers of individual colonic stromal cells in health and ulcerative colitis (UC). Marker-free transcriptional clustering revealed four distinct stromal populations in healthy colon, corresponding to myofibroblasts and three previously unknown distinct subsets of fibroblasts. These fibroblast subsets were substantially remodeled in UC compared to healthy colon: inflamed UC colon was depleted for a healthy fibroblast subpopulation associated with epithelial cell homeostasis, and enriched for a novel disease-associated subtype expressing pro-inflammatory genes. Thus, we have discovered new, molecularly distinct colonic stromal cell subtypes that are altered in human disease. Overall design: Ulcerative colitis colonic lamina propria mesenchymal cells from 3 donors. 178 single cell libraries, 7 bulk controls, 7 empty well controls. Individual donors processed as separate batches on Fluidigm C1 IFCs and pooled for sequencing (1 x Illumina HiSeq 4000 lane).
Publication Title
Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease.
Sample Metadata Fields
Disease, Subject
View Samples- Homo sapiens
- 89 Downloadable Samples
- Illumina HiSeq 2500
Description
Intestinal health is sustained by cooperation between diverse cell types, including epithelial cells, immune cells and stromal cells. Colonic stromal cells provide critical structural support but also regulate mucosal immunity, tolerance and inflammatory responses. Although mucosal stromal cells display substantial variability and plasticity, a paucity of unique genetic markers has precluded the identification of distinct stromal populations and functions. We used single-cell RNA-sequencing to uncover heterogeneity and subtype-specific markers of individual colonic stromal cells in health and ulcerative colitis (UC). Marker-free transcriptional clustering revealed four distinct stromal populations in healthy colon, corresponding to myofibroblasts and three previously unknown distinct subsets of fibroblasts. These fibroblast subsets were substantially remodeled in UC compared to healthy colon: inflamed UC colon was depleted for a healthy fibroblast subpopulation associated with epithelial cell homeostasis, and enriched for a novel disease-associated subtype expressing pro-inflammatory genes. Thus, we have discovered new, molecularly distinct colonic stromal cell subtypes that are altered in human disease. Overall design: Colonic epithelial cells from 3 healthy donors. 92 single cell libraries, 3 bulk controls, 1 empty well control. Individual donors processed as separate batches on Fluidigm C1 IFCs and pooled for sequencing (1 x Illumina HiSeq 2500 lane).
Publication Title
Structural Remodeling of the Human Colonic Mesenchyme in Inflammatory Bowel Disease.
Sample Metadata Fields
Disease, Subject
View Samples- Mus musculus
- 24 Downloadable Samples
- Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
LRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus.
Sample Metadata Fields
Age, Specimen part, Treatment
View Samples- Mus musculus
- 12 Downloadable Samples
Affymetrix Mouse Gene 2.0 ST Array (mogene20st)
Description
Strategy to repress autoimmunity and promote islet beta cell regeneration
Publication Title
LRH-1 agonism favours an immune-islet dialogue which protects against diabetes mellitus.
Sample Metadata Fields
Age, Specimen part, Treatment
View Samples- Mus musculus
- 4 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Cxcr7-/- mice die a few hours after birth. All of them display semilunar valves abnormalities, including bicuspid aortic or pulmonary valves. Those defects only become obvious before birth.
Publication Title
Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7.
Sample Metadata Fields
No sample metadata fields
View Samples- Drosophila melanogaster
- 6 Downloadable Samples
- Affymetrix Drosophila Genome 2.0 Array (drosophila2)
Description
Drosophila males double transcription of their single X chromosome to equalize X-linked gene expression with females, which carry two X chromosomes. Increased transcription requires the Male-Specific Lethal (MSL) complex. One of the primary functions of the MSL complex is thought to be enrichment of H4Ac16 on the male X chromosome, a modification linked to elevated transcription. The roX1 and roX2 RNAs are essential but redundant components of the MSL complex. Simultaneous removal of both roX RNAs reduces MSL X-localization and leads to ectopic binding of these proteins at autosomal sites and to the chromocenter. Some H4Ac16 accumulates at these ectopic sites in roX1- roX2- males, suggesting the possibility of increased expression. The global effect of roX mutations on gene expression was measured by microarray analysis. We found that expression of the X chromosome was decreased by 26% in roX1- roX2- male larvae, supporting the involvement of roX RNAs in the up-regulation of X-linked genes. This finding is broadly comparable to reports of reduced X chromosome expression following msl2 RNAi knockdown in S2 cells. In spite of strong MSL binding and H4Ac16 accumulation at autosomal sites in roX1- roX2- males, enhanced gene expression could not be detected at these sites by microarray analysis or reverse northern blotting. Thus, failure to compensate X-linked genes, rather than inappropriate up-regulation of autosomal genes at ectopic sites of MSL binding, appears to cause male lethality upon loss of roX RNAs.
Publication Title
roX RNAs are required for increased expression of X-linked genes in Drosophila melanogaster males.
Sample Metadata Fields
Sex
View Samples