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SRP064982
Mus musculus
10 Downloadable Samples
Illumina HiSeq 2500
Description
DNMT3A mutations are observed in myeloid malignancies, including myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). Here we investigated the impact of conditional hematopoietic Dnmt3a loss on disease phenotype in primary mice. Dnmt3a ablation led to a lethal, fully penetrant myeloproliferative neoplasm with myelodysplasia (MDS/MPN) characterized by marked, progressive hepatomegaly that was transplantable. We detected expanded stem/progenitor populations in the liver of Dnmt3a-ablated mice. Homing studies showed that Dnmt3a-deleted bone marrow cells preferentially migrated to the liver. Hence, in addition to the established role of Dnmt3a in regulating self-renewal, Dnmt3a regulates tissue tropism and limits myeloid progenitor expansion in vivo. Overall design: Dnmt3af/f mice (Nguyen et al) were crossed into hematopoietic-specific inducible Mx1-Cre deletor line; we examined transcriptomes from FACS-sorted LSK and GMP populations from Dnmt3af/f Mx1-Cre+ (KO) and Dnmt3af/f Mx1-Cre- (CTRL) animals at 12 months of age
Publication Title
Dnmt3a regulates myeloproliferation and liver-specific expansion of hematopoietic stem and progenitor cells.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 9 Downloadable Samples
Description
To define target genes of the intestine-restricted transcription factor (TF) CDX2 in intestinal stem cells, we performed chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-Seq). We used RNA-sequencing to profile gene expression changes during cell differentiation from mouse intestinal stem cells to mature villus cells, as well as genes perturbed in intestinal stem cells upon loss of Cdx2. We find thousands of genes that change in expression during cell differentiation, including known stem cell and mature markers. Upon loss of Cdx2, hundreds of genes are up and down-regulated in intestinal stem cells, some of which are also bound by CDX2 nearby and constitute candidate direct target genes. Overall design: CDX2 ChIP-Seq analysis of isolated mouse intestinal stem cells. RNA seq analysis of control mouse villus cells, control intestinal stem cells and Cdx2-deleted intestinal stem cells.
Publication Title
Distinct Processes and Transcriptional Targets Underlie CDX2 Requirements in Intestinal Stem Cells and Differentiated Villus Cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Danio rerio
- 12 Downloadable Samples
Affymetrix Zebrafish Genome Array (zebrafish)
Description
Microarray data allowed detection of genes that are induced by light in the zebrafish pineal gland
Publication Title
The light-induced transcriptome of the zebrafish pineal gland reveals complex regulation of the circadian clockwork by light.
Sample Metadata Fields
Sex, Specimen part, Treatment, Time
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
In this data, we examined Transcriptome detection and expression in 8 samples of Retinoblastoma. We found a central core shared by all samples .
Publication Title
Discovery of a transcriptomic core of genes shared in 8 primary retinoblastoma with a novel detection score analysis.
Sample Metadata Fields
Disease
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Here we describe a method for fabricating a primary human Small Intestine-on-a-Chip (Intestine Chip) containing epithelial cells isolated from healthy regions of intestinal biopsies. The primary epithelial cells are expanded as 3D organoids, dissociated, and cultured on a porous membrane within a microfluidic device with human intestinal microvascular endothelium cultured in a parallel microchannel under flow and cyclic deformation. In the Intestine Chip, the epithelium forms villi-like projections lined by polarized epithelial cells that undergo multi-lineage differentiation similar to that of intestinal organoids, however, these cells expose their apical surfaces to an open lumen and interface with endothelium. Transcriptomic analysis also indicates that the Intestine Chip more closely mimics whole human duodenum in vivo when compared to the duodenal organoids used to create the chips. Because fluids flowing through the lumen of the Intestine Chip can be collected continuously, sequential analysis of fluid samples can be used to quantify nutrient digestion, mucus secretion and establishment of intestinal barrier function over a period of multiple days in vitro. The Intestine Chip therefore may be useful as a research tool for applications where normal intestinal function is crucial, including studies of metabolism, nutrition, infection, and drug pharmacokinetics, as well as personalized medicine.
Publication Title
Development of a primary human Small Intestine-on-a-Chip using biopsy-derived organoids.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U219 Array (hgu219)
Description
Multiple myeloma (MM) cells were treated with the BET inhibitor CPI203 alone and in combination with lenalidomide plus dexamethasone in vitro and in vivo (mouse xenograft).
Publication Title
The BET bromodomain inhibitor CPI203 improves lenalidomide and dexamethasone activity in <i>in vitro</i> and <i>in vivo</i> models of multiple myeloma by blockade of Ikaros and MYC signaling.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- 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- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Respiratory innate immunity requires alveolar macrophages, which are specifically targeted by the S. aureus toxin alpha toxin. These data compare the response of alveolar macrophages to S. aureus with or without alpha toxin neutralization.
Publication Title
S. aureus Evades Macrophage Killing through NLRP3-Dependent Effects on Mitochondrial Trafficking.
Sample Metadata Fields
Sex, Age, Specimen part, Treatment
View Samples- Mus musculus
- 20 Downloadable Samples
- NextSeq 500
Description
The generation of induced pluripotent stem cells (iPSCs) and the direct conversion approach provide an invaluable resource of cells for disease modeling, drug screening, and patient-specific cell-based therapy. However, while iPSCs are stable and resemble ESCs in their transcriptome, methylome and function, the vast majority of the directly converted cells represent an incomplete reprogramming state as evident by their aberrant transcriptome and transgene dependency. This raises the question of whether complete and stable nuclear reprogramming can be achieved only in pluripotent cells. Here we demonstrate the generation of stable and fully functional induced trophoblast stem cells (iTSCs) by transient expression of Gata3, Tfap2c and Eomes. Similarly to iPSCs, iTSCs underwent a complete and stable reprogramming process as assessed by transcriptome and methylome analyses and functional assays such as the formation of hemorrhagic lesion and placenta contribution. Careful examination of the conversion process indicated that the cells did not go through a transient pluripotent state. These results suggest that complete nuclear reprograming can be attained in non-pluripotent cells. Overall design: Technical duplicates of 10 samples
Publication Title
Extensive Nuclear Reprogramming Underlies Lineage Conversion into Functional Trophoblast Stem-like Cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 16 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
OBJECTIVE: Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterize the role of tumor-initiating cells (T-ICs) and signaling pathways involved in sorafenib resistance. DESIGN: HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: 1) Role of T-ICs by in vitro sphere formation and in vivo tumorigenesis assays using NOD/SCID mice, 2) Activation of alternative signaling pathways and 3) Efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, qRT-PCR) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in 2 independent cohorts. RESULTS: Sorafenib-acquired resistance tumors showed significant enrichment of T-ICs (164 cells needed to create a tumor) vs. sorafenib-sensitive tumors (13400 cells) and non-treated tumors (1292 cells), p<0.001. Tumors with sorafenib-acquired resistance were enriched with IGF and FGF signaling cascades (FDR<0.05). In vitro, cells derived from sorafenib-acquired resistant tumors and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumor growth and improved survival in sorafenib-resistant tumors. A sorafenib-resistance 175-gene signature was characterized by enrichment of progenitor-cell features, aggressive tumoral traits and predicted poor survival in 2 cohorts (n=442 HCC patients). CONCLUSION: Acquired resistance to sorafenib is driven by tumor initiating cells with enrichment of progenitor markers and activation of IGF and FGF signaling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression.
Publication Title
Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma.
Sample Metadata Fields
No sample metadata fields
View Samples