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GSE29459
Homo sapiens
1 Downloadable Sample
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
We used microarrays to observe the global gene expression in hematopoietic stem and projenitor cells during ex vivo culture with DMSO (Blank) or with Garcinol (GAR) and identified distinct classes of up or down-regulated genes.
Publication Title
Ex vivo expansion of human hematopoietic stem cells by garcinol, a potent inhibitor of histone acetyltransferase.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Extracellular Acidic pH Activates the Sterol Regulatory Element-Binding Protein 2 to Promote Tumor Progression.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus, Homo sapiens
- 16 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The pre-metastatic niche is a pre-determined site of metastases, awaiting the influx of tumor cells. Here we demonstrate that the calcineurin-NFAT pathway is activated specifically in lung endothelium prior to the detection of tumor cells that preferentially metastasize to the lung. We previously showed that DSCR-1 functions in a negative feedback loop to attenuate calcineurin signaling. Upregulation of the calcineurin pathway via loss of Dscr-1 leads to a significant increase in lung metastasis due to the increased expression of a newly identified NFAT target, Angiopoietin (Ang)-2. An increase in VEGF levels specifically in the lung versus other organ microenvironments triggers a threshold of calcineurin-NFAT signaling that transactivates Ang2 in lung endothelium. Further, we demonstrate that overexpression of DSCR-1 or the Ang-2 receptor, soluble Tie2, prevents activation of the lung endothelium inhibiting lung metastases in our mouse models. Our studies provide insights into mechanisms underlying angiogenesis in the pre-metastatic niche and offers novel targets for lung metastases.
Publication Title
The calcineurin-NFAT-angiopoietin-2 signaling axis in lung endothelium is critical for the establishment of lung metastases.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The conditions of the tumor microenvironment, such as hypoxia and nutrient starvation, play critical roles in cancer progression. However, the role of acidic extracellular pH in cancer progression is not studied as extensively as that of hypoxia. Here, we show that extracellular acidic pH (pH 6.8) triggered activation of sterol regulatory element-binding protein 2 (SREBP2) by stimulating nuclear translocation and promoter binding to its targets along with intracellular acidification. Interestingly, inhibition of SREBP2, but not SREBP1, suppressed the upregulation of low pH-induced cholesterol biosynthesis-related genes. Moreover, acyl-CoA synthetase short-chain family member 2 (ACSS2), a direct SREBP2 target, provided a growth advantage to cancer cells under acidic pH. Furthermore, acidic pH-responsive SREBP2 target genes were associated with reduced overall survival of cancer patients. Thus, our findings show that SREBP2 is a key transcriptional regulator of metabolic genes and progression of cancer cells, partly in response to extracellular acidification.
Publication Title
Extracellular Acidic pH Activates the Sterol Regulatory Element-Binding Protein 2 to Promote Tumor Progression.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 17 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Dynamically and epigenetically coordinated GATA/ETS/SOX transcription factor expression is indispensable for endothelial cell differentiation.
Sample Metadata Fields
Specimen part, Time
View Samples- Homo sapiens
- 18 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Human embryonic stem cells (hESCs) are a powerful tool for modeling regenerative therapy. To search for the genes that promote hematopoietic development from human pluripotent stem cell, we overexpressed a list of hematopoietic regulator genes in human pluripotent stem cell-derived CD34+CD43- endothelial cells (ECs) enriched in hemogenic endothelium. Among genes tested, only SOX17, a gene encoding a transcription factor of the SOX family, promoted cell growth and supported expansion of CD34+CD43+CD45-/low cells expressing a hemogenic endothelial maker VE-cadherin. SOX17 was highly expressed in CD34+CD43- ECs but at a low level in CD34+CD43+CD45- pre-hematopoietic progenitor cells (pre-HPCs) and CD34+CD43+CD45+ HPCs. SOX17-overexpressing cells formed sphere-like colonies and generated few hematopoietic progenies. However, they retained hemogenic potential and gave rise to hematopoietic progenies upon inactivation of SOX17. Global gene expression analyses revealed that the CD34+CD43+CD45-/low cells expanded upon overexpression of SOX17 are hemogenic endothelium-like cells developmentally placed between ECs and pre-HPCs. Of interest, SOX17 also reprogrammed both pre-HPCs and HPCs into hemogenic endothelium-like cells. Genome-wide mapping of SOX17 revealed that SOX17 directly activates transcription of key regulator genes for vasculogenesis, hematopoiesis, and erythrocyte differentiation. Depletion of SOX17 in CD34+CD43- ECs severely compromised their hemogenic activity. These findings suggest that SOX17 plays a critical role in priming hemogenic potential in ECs, thereby regulates hematopoietic development from hESCs.
Publication Title
Role of SOX17 in hematopoietic development from human embryonic stem cells.
Sample Metadata Fields
Specimen part, Disease
View Samples- Homo sapiens
- 18 Downloadable Samples
Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Overexpression of transcription factor Sox17 in human ES cells-derived endothelial cells and hematopoietic cells enhances expansion of hemogenic endothelium-like cells.
Publication Title
Role of SOX17 in hematopoietic development from human embryonic stem cells.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 17 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Although differentiation of mice embryonic stem cells into vascular endothelial cells (ECs) gives a model for investigating molecular mechanisms of vascular development in vivo, temporal dynamics of gene expressions and chromatin modifications have not been studied until now. Here, we interrogated transcriptome and two histone modifications, H3K4me3 and H3K27me3, with a genome-wide scale during ECs differentiation and elucidated epigenetic switch peculiar to ECs. We find Gata2, Fli1, Sox7, and Sox18 are master regulators from genetic and epigenetic data, these genes were induced after Etv2 activation. These genes have specific histone modification pattern which is repressed by H3K27me3 modification at Flk-sorted mesoderm and changed to the bivalent (H3K4me3 and H3K27me3 both positive) state rapidly after vascular endothelial cells growth factor (VEGF) stimuli. Using a previously reported ECs differentiation model, we demonstrate that four transcription factors are critical for ECs specific gene expressions and efficient differentiation. Moreover, from knockdown experiments using si-RNA, we discovered these factors inhibited not only TGF signaling pathway, that is endothelial mesenchymal transition pathway, but also other near lineage commitment, including blood cells, skeletal muscle cells, vascular smooth muscle cells, and cardiomyocytes. We further identify each factor specific target genes during ECs differentiation by microarray, including both activating and repressing genes. Together, our findings from a detailed epigenetic approach provide a basic understanding temporal regulated chromatin signatures and resulting gene expression profile during ECs commitment, which is applicable to other models of differentiation and production of mature and long lasting ECs for regenerative medicine.
Publication Title
Dynamically and epigenetically coordinated GATA/ETS/SOX transcription factor expression is indispensable for endothelial cell differentiation.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 10 Downloadable Samples
Illumina HiSeq 2500
Description
The balance between self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPCs) maintains hematopoietic homeostasis, failure of which can lead to hematopoietic disorder. HSPC fate is controlled by signals from the bone marrow niche resulting in alteration of the stem cell transcription network. Regnase-1, a member of the CCCH zinc finger protein family possessing RNAse activity, mediates post-transcriptional regulatory activity through degradation of target mRNAs. The precise function of Regnase-1 has been explored in inflammation-related cytokine expression but its function in hematopoiesis has not been elucidated. To clarify the role of Regnase-1 for hematopoiesis, we performed gene expression analysis on sorted HSC from control and Regnase1 null mice. Overall design: Bone marrow cells were obtained from femur of individual eight-week old Vav1-iCre; Reg1flox/flox mice (Reg1?/?, case) and control Reg1flox/flox mice (Reg1flox/flox ,control). RNAseq analyses were performed on HSCs (Lin- ScaI+ cKit+ CD34- Flt3- cells) purified by flow cytometry sorting.
Publication Title
Regnase-1-mediated post-transcriptional regulation is essential for hematopoietic stem and progenitor cell homeostasis.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 12 Downloadable Samples
- Illumina HiSeq 1500
Description
Background: Blau syndrome, or early-onset sarcoidosis, is a juvenile-onset systemic granulomatosis associated with a mutation in Nucleotide-binding oligomerization domain 2 (NOD2). The underlying mechanisms of Blau syndrome leading to autoinflammation are still unclear, and there is currently no effective specific treatment for Blau syndrome. Objectives: To elucidate the mechanisms of autoinflammation in Blau syndrome, we sought to clarify the relation between disease associated-mutant NOD2 and the inflammatory response in human samples. Methods: Blau syndrome-specific induced pluripotent stem cells (iPSCs) lines were established. To precisely evaluate the in vitro phenotype of iPSC-derived cells, the disease-associated NOD2 mutation of iPSCs was corrected using a CRISPR/Cas9 system. We also introduced the same NOD2 mutation into a control iPSC line. These isogenic iPSCs were then differentiated into monocytic cell lineages, and the status of NF-?B pathway and proinflammatory cytokine secretion were investigated. Results: We focused on the signals that upregulate the expression of NOD2, especially IFN-? signaling. IFN-? treatment of NOD2-mutant macrophages induced ligand-independent NF-?B activation and proinflammatory cytokine production. IFN-? treatment acted as a priming signal through the up-regulation of NOD2 protein and recruitment of NOD2 on the basement membrane. Conversely, the production of proinflammatory cytokines by MDP, a ligand of NOD2, was decreased in mutant macrophages. Conclusions: Our data support the significance of ligand-independent autoinflammation in the pathophysiology of Blau syndrome. Our comprehensive isogenic disease-specific iPSC panel provides a useful platform for probing therapeutic and diagnostic clues for the treatment of Blau syndrome patients. Overall design: RNA-sequencing was conducted to identify the genes expressed in reponse to stimulation in different manners between WT and MT cells
Publication Title
Pluripotent stem cell models of Blau syndrome reveal an IFN-γ-dependent inflammatory response in macrophages.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Subject
View Samples