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SRP056125
Mus musculus
6 Downloadable Samples
Illumina HiSeq 2000
Description
Context dependent molecular cues shape the formation of the cerebral vascular network and the function of the blood-brain barrier (BBB). The Wnt/ß-catenin pathway is orchestrating CNS vascular development, but downstream mediators have not been characterized. Here we generated an endothelial cell-specific R26-Axin1 overexpression (AOE) mouse model to inhibit Wnt/ß-catenin signaling. In AOE mice we discovered that blockade of Wnt/ß-catenin pathway leads to premature regression and remodeling without compromising BBB integrity. Importantly, by comparing transcriptomes of endothelial cells from wildtype and AOE mice, we identified ADAMTSL2 as a novel Wnt/ß-catenin-induced, secreted factor, important for stabilizing the BBB during development. Zebrafish loss-of-function and gain-of-function models, further demonstrated that ADAMTSL2 is crucial for normal vascular development and could rescue vascular phenotypes in AOE zebrafish brains. In conclusion, the studies presented here reveal a hitherto unrecognized role of ADAMTSL2 as an endothelial cell-specific mediator of Wnt/ß-catenin signaling during CNS vascular development and BBB-formation. Overall design: Examination of expression changes in mouse brain endothelial cells when overexpressing Axin1
Publication Title
Disruption of the Extracellular Matrix Progressively Impairs Central Nervous System Vascular Maturation Downstream of β-Catenin Signaling.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 4 Downloadable Samples
- Illumina HiSeq 2500
Description
Using complementary forms of high dimensional profiling we define differences in CD45+ cells from syngeneic mouse tumors that either grow progressively or eventually reject following immune checkpoint therapy (ICT). Unbiased assessment of gene expression of tumor infiltrating cells by single cell RNA sequencing (scRNAseq) and longitudinal assessment of cellular protein expression by mass cytometry (CyTOF) revealed significant remodeling of both the lymphoid and myeloid intratumoral compartments. Surprisingly, we observed multiple subpopulations of monocytes/macrophages distinguishable by the combinatorial presence or absence of CD206, CX3CR1, CD1d and iNOS, markers of different macrophage activation states that change over time during ICT in a manner partially dependent on IFN?. Both the CyTOF data and additional analysis of scRNAseq data support the hypothesis that macrophage polarization/activation results from effects on circulatory monocytes/early macrophages entering tumors rather than on pre-polarized mature intratumoral macrophages. Thus, ICT induces transcriptional and functional remodeling of both myeloid and lymphoid compartments. Overall design: Droplet-based 3' end massively parallel single-cell RNA sequencing was performed by encapsulating sorted live CD45+ tumor infiltrating cells into droplets and libraries were prepared using Chromium Single Cell 3' Reagent Kits v1 according to manufacturer's protocol (10x Genomics). The generated scRNAseq libraries were sequenced using an Illumina HiSeq2500.
Publication Title
High-Dimensional Analysis Delineates Myeloid and Lymphoid Compartment Remodeling during Successful Immune-Checkpoint Cancer Therapy.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 85 Downloadable Samples
Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
We examined if pediatric AMLs rank-ordered according to C/EBP expression showed the activation of similar pathways. AML samples were dichotomized into groups including the upper quartile (Q1) and the lower three quartiles (Q2-4) according to their C/EBP expression values. Moreover, AML samples were associated to French-American-British (FAB) classification.
Publication Title
CREB engages C/EBPδ to initiate leukemogenesis.
Sample Metadata Fields
Specimen part, Disease
View Samples- Danio rerio
- 10 Downloadable Samples
- Affymetrix Zebrafish Genome Array (zebrafish)
Description
To examine the role of CREB overexpression in hematopoiesis, we created a model of leukemia in zebrafish by overexpressing the human CREB in the myeloid hematopoietic lineage. Whole transcriptome analysis of kidney-marrow revealed 171 genes differently expressed between CREB- and control-zebrafish (five per group). Interestingly, the integration of this signature with human deposited data revealed that this tumor resembled a human AML at transcriptome level.
Publication Title
CREB engages C/EBPδ to initiate leukemogenesis.
Sample Metadata Fields
Specimen part
View Samples- Danio rerio
- 4 Downloadable Samples
- NextSeq 500
Description
Comparison of the meis2b+ and the meis2b- halves of the atrium of the adult zebrafish atrium reveals the existence of two different transcriptional domains. These two domains analogous to that of the two atria in terrestrial vertebrates Overall design: To determine the expression profiles of the Tg(meis2b-reporter)-positive vs -negative atrial compartments, a total of 6 hearts of 3 mpf Tg(meis2b-reporter) zebrafish were micro-dissected. A total of 4 pools were made: the first two pools, each contained 3 Tg(meis2b-reporter)-positive atrial compartments, and the other two contained the Tg(meis2b-reporter)-negative halves.
Publication Title
Distinct myocardial lineages break atrial symmetry during cardiogenesis in zebrafish.
Sample Metadata Fields
Age, Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 82 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
gene expression database and algorithm to define cell expression modules
Publication Title
Identifying gene expression modules that define human cell fates.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 20 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The mechanism of CD4(+) T cell depletion during chronic human immunodeficiency virus type 1 (HIV-1) infection remains unknown. Many studies suggest a significant role for chronic CD4(+) T cell activation. We assumed that the pathogenic process of excessive CD4(+) T cell activation would be reflected in the transcriptional profiles of activated CD4(+) T cells. Here we demonstrate that the transcriptional programs of in vivo activated CD4(+) T cells from untreated HIV(+) individuals are clearly different from those activated CD4(+) T cells from HIV(-) individuals. We observed a dramatic up-regulation of cell cycle-associated and interferon-stimulated transcripts in activated CD4(+) T cells of untreated HIV(+) individuals. Furthermore, we find an enrichment of proliferative and Type I interferon-responsive transcription factor binding sites in the promoters of genes that are differentially expressed in activated CD4(+) T cells of untreated HIV(+) individuals compared to HIV(-) individuals. We confirm these findings by examination of in vivo activated CD4(+) T cells. Taken together, these results suggest that activated CD4(+) T cells from untreated HIV(+) individuals are in a hyper-proliferative state that is modulated by Type I interferons. From these results, we propose a new model for CD4(+) T cell depletion during chronic HIV-1 infection.
Publication Title
Chronic CD4+ T-cell activation and depletion in human immunodeficiency virus type 1 infection: type I interferon-mediated disruption of T-cell dynamics.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 5 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
ZNF521 is a multiple zinc finger transcription factor previously identified because abundantly and selectively expressed in normal CD34+ hematopoietic stem and progenitor cells. From microarray datasets, aberrant expression of ZNF521 has been reported in both pediatric and adult acute myeloid leukemia (AML) patients with MLL gene rearrangements. However, a proper validation of microarray data is lacking, likewise ZNF521 contribution in MLL-rearranged AML is still uncertain. In this study, we show that ZNF521 is significantly upregulated in MLL translocated AML patients from a large pediatric cohort, regardless of the type of MLL translocations such as MLL-AF9, MLL-ENL, MLL-AF10 and MLL-AF6 fusion genes. Our in vitro functional studies demonstrate that ZNF521 play a critical role in the maintenance of the undifferentiated state of MLL-rearranged cells. Furthermore, analysis of the ZNF521 gene promoter region shows that ZNF521 is a direct downstream target of both MLL-AF9 and MLL-ENL fusion proteins. Gene expression profiling of MLL-AF9-rearranged THP-1 cells after depletion of ZNF521 reveals correlation with several expression signatures including stem cell-like and MLL fusion dependent programs. These data suggest that MLL fusion proteins activate ZNF521 expression to maintain the undifferentiated state and contribute to leukemogenesis.
Publication Title
ZNF521 sustains the differentiation block in MLL-rearranged acute myeloid leukemia.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 32 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
Alternative promoters (APs) occur in >30% protein-coding genes and contribute to proteome diversity. However, large-scale analyses of AP regulation are lacking, and little is known about their potential physiopathologic significance. To better understand the transcriptomic impact of estrogens, which play a major role in breast cancer, we analyzed gene and AP regulation by estradiol in MCF7 cells using pan-genomic exon arrays. We thereby identified novel estrogen-regulated genes, and determined the regulation of AP-encoded transcripts in 150 regulated genes. In <30% cases, APs were regulated in a similar manner by estradiol, while in >70% cases, they were regulated differentially. The patterns of AP regulation correlated with the patterns of estrogen receptor (ER) and CCCTC-binding factor (CTCF) binding sites at regulated gene loci. Interestingly, among genes with differentially regulated APs, we identified cases where estradiol regulated APs in an opposite manner, sometimes without affecting global gene expression levels. This promoter switch was mediated by the DDX5/DDX17 family of ER coregulators. Finally, genes with differentially regulated promoters were preferentially involved in specific processes (e.g., cell structure and motility, and cell cycle). We show in particular that isoforms encoded by the NET1 gene APs, which are inversely regulated by estradiol, play distinct roles in cell adhesion and cell cycle regulation, and that their expression is differentially associated with prognosis in ER+ breast cancer. Altogether, this study identifies the patterns of AP regulation in estrogen-regulated genes, demonstrates the contribution of AP-encoded isoforms to the estradiol-regulated transcriptome, as well as their physiopathologic significance in breast cancer.
Publication Title
Estrogen regulation and physiopathologic significance of alternative promoters in breast cancer.
Sample Metadata Fields
Disease, Disease stage, Cell line, Time
View Samples- Mus musculus
- 48 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Renal gene expression analysis was performed in mouse strains with different propensity to develop progressive chronic kidney disease (CKD) after subtotal nephrectomy: the FVB strain which is spontaneously highly predisposed to CKD and the C57BL/6 which is spontaneously not predisposed to CKD. Subtotal nephrectomy (Nx) is normally initially compensated by proliferative tissue repair (2 days after nephrectomy). After this initial proliferation follows a quiescent period (28 days after NX). Finally, specifically in the sensitive strain there is lesion onset (53 days after Nx). Gene expression was monitored on RNA from whole kidneys from different mouse strains Sham operated or Nephrectomised at three different time-points.
Publication Title
Signaling pathways predisposing to chronic kidney disease progression.
Sample Metadata Fields
Time
View Samples