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SRP013504
Homo sapiens
3 Downloadable Samples
Description
The TCF7L2 transcription factor is linked to a variety of human diseases, including type 2 diabetes and cancer. One mechanism by which TCF7L2 could influence expression of genes involved in diverse diseases is by binding to distinct regulatory regions in different tissues. To test this hypothesis, we performed ChIP-seq for TCF7L2 in 6 human cell lines. We identified 116,000 non-redundant TCF7L2 binding sites, with only 1,864 sites common to the 6 cell lines. Using ChIP-seq, we showed that many genomic regions that are marked by both H3K4me1 and H3K27Ac are also bound by TCF7L2, suggesting that TCF7L2 plays a critical role in enhancer activity. Bioinformatic analysis of the cell type-specific TCF7L2 binding sites revealed enrichment for multiple transcription factors, including HNF4alpha and FOXA2 motifs in HepG2 cells and the GATA3 motif in MCF7 cells. ChIP-seq analysis revealed that TCF7L2 co-localizes with HNF4alpha and FOXA2 in HepG2 cells and with GATA3 in MCF7 cells. Interestingly, in MCF7 cells the TCF7L2 motif is enriched in most TCF7L2 sites but is not enriched in the sites bound by both GATA3 and TCF7L2. This analysis suggested that GATA3 might tether TCF7L2 to the genome at these sites. To test this hypothesis, we depleted GATA3 in MCF7 cells and showed that TCF7L2 binding was lost at a subset of sites. RNA-seq analysis suggested that TCF7L2 represses transcription when tethered to the genome via GATA3. Our studies demonstrate a novel relationship between GATA3 and TCF7L2, and reveal important insights into TCF7L2-mediated gene regulation. Overall design: RNAseq analysis of MCF7 cells transfected with siCONTROL, siTCF7L2 or siGATA3. ChIP-seq analysis of H3K27ac, H3K4me1, H3K27me3, H3K9me3 in MCF7 cells; H3K4me1 and H3K27ac in HCT116 cells.
Publication Title
Cell type-specific binding patterns reveal that TCF7L2 can be tethered to the genome by association with GATA3.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 6 Downloadable Samples
- IlluminaHiSeq2000
Description
We have compared the genome-wide effects on the transcriptome after treatment with ICG-001 (the specific CBP inhibitor) versus C646, a compound that competes with acetyl-coA for the Lys-coA binding pocket of both CBP and p300. We found that both drugs cause large-scale changes in the transcriptome of HCT116 colon cancer cells and PANC1 pancreatic cancer cells, and reverse some tumor-specific changes in gene expression. Interestingly, although the epigenetic inhibitors affect cell cycle pathways in both the colon and pancreatic cancer cell lines, the WNT signaling pathway was affected only in the colon cancer cells. Notably, WNT target genes were similarly down-regulated after treatment of HCT116 with C646 as with ICG-001. Overall design: To identify genes affected by direct targeting of a component of the transcriptional complex implicated in WNT regulation, we used siRNAs to knockdown TCF7L2 in PANC1 cells. Cells were treated with control siRNAs or siRNAs specific for TCF7L2 and RNA was analyzed by RNA-seq.
Publication Title
Three-dimensional analysis reveals altered chromatin interaction by enhancer inhibitors harbors TCF7L2-regulated cancer gene signature.
Sample Metadata Fields
No sample metadata fields
View Samples- Rattus norvegicus
- 6 Downloadable Samples
Affymetrix Rat Genome 230 2.0 Array (rat2302)
Description
Maternal obesity during the pre-implantation period leads to a pro-inflammatory milieu in the ovaries. We conducted a global transcriptomic profiling in ovaries from TEN fed rats during the pre-implantation period. Microarray analysis revealed that obesity lead to increased expression of genes related to inflammation, decreased glucose transporters, and dysregulation of ovarian function-related genes in the ovaries. Our results suggest maternal obesity led to an up-regulation of inflammatory genes and Egr-1 protien expression in peri-implantation ovarian tissue, and a concurrent down-regulation of glucose transporters mRNA and AKT and PI3K protein levels.
Publication Title
Maternal obesity is associated with ovarian inflammation and upregulation of early growth response factor 1.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 7 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Telomere dysfunction drives aberrant hematopoietic differentiation and myelodysplastic syndrome.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 7 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Telomere dysfunctional CMP/GMP have deregulated pathways that are associated with DNA damage signaling
Publication Title
Telomere dysfunction drives aberrant hematopoietic differentiation and myelodysplastic syndrome.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 53 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Rhabdoid tumors (RT) are aggressive tumors characterized by genetic loss of SMARCB1 (SNF5, INI-1), a component of the SWI/SNF chromatin remodeling complex. No effective treatment is currently available. This study seeks to shed light on the SMARCB1-mediated pathogenesis of RT and to discover potential therapeutic targets. Global gene expression of 10 RT was compared with 12 cellular mesoblastic nephromas, 16 clear cell sarcomas of the kidney, and 15 Wilms tumors. 114 top genes were differentially expressed in RT (p<0.001, fold change >2 or <0.5). Among these were down-regulation of SMARCB1 and genes previously associated with SMARCB1 (ATP1B1, PTN, DOCK4, NQO1, PLOD1, PTP4A2, PTPRK). 28/114 top differentially expressed genes were involved with neural or neural crest development and were all sharply down-regulated. This was confirmed by Gene Set Enrichment Analysis (GSEA). Neural and neural crest stem cell marker proteins SOX10, ID3, CD133 and Musashi were negative by immunohistochemistry, whereas Nestin was positive. Decreased expression of CDKN1A, CDKN1B, CDKN1C, CDKN2A, and CCND1 was identified, while MYC-C was upregulated. GSEA of independent gene sets associated with bivalent histone modification and polycomb group targets in embryonic stem cells demonstrated significant negative enrichment in RT. Several differentially expressed genes were associated with tumor suppression, invasion and metastasis, including SPP1 (osteopontin), COL18A1 (endostatin), PTPRK, and DOCK4. We conclude that RTs arise within early progenitor cells during a critical developmental window in which loss of SMARCB1 directly results in repression of neural development, loss of cyclin dependent kinase inhibition, and trithorax/polycomb dysregulation.
Publication Title
Rhabdoid tumor: gene expression clues to pathogenesis and potential therapeutic targets.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 3 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Goal: To compare the gene expression profiles from pediatric patients with each other, with those reported in adults and in those related to exosomes.
Publication Title
Differential gene expression of soluble CD8+ T-cell mediated suppression of HIV replication in three older children.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 144 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
The gene expression patterns of favorable histology Wilms tumors (FHWT) that relapsed were compared with those that did not relapse using oligonucleotide arrays
Publication Title
Predicting relapse in favorable histology Wilms tumor using gene expression analysis: a report from the Renal Tumor Committee of the Children's Oncology Group.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina Genome Analyzer
Description
Diffuse intrinsic pontine glioma (DIPG) is an incurable pediatric brain tumor, resulting in the death of 200-300 children each year in the United States. Recently it was discovered that approximately 25% of all DIPG cases harbor activating mutations in ACVR1, a gene that encodes Activin A receptor (ALK2), a receptor in the bone morphogenetic protein (BMP) pathway, and that DIPGs with ALK2 mutations commonly harbor an H3.1K27M mutation. Herein, we used the RCAS/TVA retroviral system to study the effects of ACVR1 mutations and H3.1K27M on DIPG pathogenesis. In vitro expression of R206H ACVR1 with and without H3.1K27M in nestin-expressing brainstem progenitors resulted in upregulation of mesenchymal markers and gene set enrichment analysis (GSEA) revealed Stat3 pathway activation. Neonatal expression of ACVR1 R206H or G328V in combination with H3.1K27M and p53 deletion in nestin-expressing brainstem progenitors induced glioma-like lesions expressing mesenchymal markers with Stat3 activation but was not sufficient for full gliomagenesis. In combination with platelet-derived growth factor A (PDGFA) signaling, ACVR1 R206H and H3.1K27M significantly decreased survival and increased tumor incidence. We demonstrate that targeting the BMP signaling pathway may be an effective therapeutic strategy to treat ACVR1 R206H mutant DIPGs. Exogenous Noggin expression at tumor initiation significantly increased tumor latency and treatment of ACVR1 R206H mutant murine DIPGs with LDN212854, an ACVR1 inhibitor, significantly prolonged their survival. We confirm relevance of our model to the human disease as human DIPG models with ACVR1 mutations were also sensitive to treatment with LDN212854 in vitro. Altogether, our studies demonstrate that ACVR1 R206H and H3.1K27M promote tumor initiation, accelerate gliomagenesis, promote a mesenchymal profile in part due to Stat3 activation, and identify LDN212854 as a promising compound to treat children with DIPG. Overall design: We use RNAseq to study the transcriptomal effects of ACVR1 WT or R206H ACVR1 mutation alone and in combination with H3.1K27M mutation on murine nestin-expressing brainstem progenitors at P3-5 (using RCAS/TVA). Key findings were validated by Real-Time PCR.
Publication Title
ACVR1 R206H cooperates with H3.1K27M in promoting diffuse intrinsic pontine glioma pathogenesis.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 55 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
The goal of this study is to identify downstream pathways, diagnostic markers, and potential therapeutic targets for IFS/CMN.
Publication Title
Mediators of receptor tyrosine kinase activation in infantile fibrosarcoma: a Children's Oncology Group study.
Sample Metadata Fields
Specimen part
View Samples