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GSE57633
Homo sapiens
3 Downloadable Samples
Illumina HumanWG-6 v3.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Stability of gene expression and epigenetic profiles highlights the utility of patient-derived paediatric acute lymphoblastic leukaemia xenografts for investigating molecular mechanisms of drug resistance.
Sample Metadata Fields
Sex
View Samples- Homo sapiens
- 3 Downloadable Samples
- Illumina HumanWG-6 v3.0 expression beadchip
Description
Background: Patient-derived tumour xenografts are an attractive model for preclinical testing of anti-cancer drugs. Insights into tumour biology and biomarkers predictive of responses to chemotherapeutic drugs can also be gained from investigating xenograft models. As a first step towards examining the equivalence of epigenetic profiles between xenografts and primary tumours in paediatric leukaemia, we performed genome-scale DNA methylation and gene expression profiling on a panel of 10 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) tumours that were stratified by prednisolone response. Results: We found high correlations in DNA methylation and gene expression profiles between matching primary and xenograft tumour samples with Pearsons correlation coefficients ranging between 0.85 and 0.98. In order to demonstrate the potential utility of epigenetic analyses in BCPALL xenografts, we identified DNA methylation biomarkers that correlated with prednisolone responsiveness of the original tumour samples. Differential methylation of CAPS2, ARHGAP21, ARX and HOXB6 were confirmed by locus specific analysis. We identified 20 genes showing an inverse relationship between DNA methylation and gene expression in association with prednisolone response. Pathway analysis of these genes implicated apoptosis, cell signalling and cell structure networks in prednisolone responsiveness. Conclusions: The findings of this study confirm the stability of epigenetic and gene expression profiles of paediatric BCP-ALL propagated in mouse xenograft models. Further, our preliminary investigation of prednisolone sensitivity highlights the utility of mouse xenograft models for preclinical development of novel drug regimens with parallel investigation of underlying gene expression and epigenetic responses associated with novel drug responses.
Publication Title
Stability of gene expression and epigenetic profiles highlights the utility of patient-derived paediatric acute lymphoblastic leukaemia xenografts for investigating molecular mechanisms of drug resistance.
Sample Metadata Fields
Sex
View Samples- Homo sapiens
- 3 Downloadable Samples
- Illumina human-6 v2.0 expression beadchip
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Patterns of histone H3 lysine 27 monomethylation and erythroid cell type-specific gene expression.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 3 Downloadable Samples
- Illumina human-6 v2.0 expression beadchip
Description
ERYTHROID CELL-TYPE SPECIFIC GENE EXPRESSION
Publication Title
Patterns of histone H3 lysine 27 monomethylation and erythroid cell type-specific gene expression.
Sample Metadata Fields
Cell line
View Samples- Mus musculus
- 24 Downloadable Samples
Description
Differentiation of naïve CD4+ T cells into effector (Th1, Th2 and Th17) and induced regulatory (iTreg) T cells requires lineage-specifying transcription factors and epigenetic modifications that allow appropriate repression or activation of gene transcription. The epigenetic silencing of cytokine genes is associated with the repressive H3K27 trimethylation mark, mediated by Ezh2 or Ezh1 methyltransferase components of the polycomb repressive complex 2 (PRC2). EZH2 over-expression and activating mutations are implicated in tumorigenesis and correlate with poor prognosis in several tumor types 35. This spurred the development of EZH2 inhibitors which, by inducing tumor cell growth arrest and cell death, show therapeutic promise in cancer. A role for Ezh2 in suppressing Th1 and Th2 cytokine production and survival has recently been reported. It is not entirely clear whether Ezh2-PRC2 plays a role in H3K27me3 in cytokine loci in naïve CD4+ T cells and whether H3K27me3 has a non-redundant role in T helper cell lineage differentiation and survival. Here, we investigate the effects of T cell-specific Ezh2 deletion to determine the role that Ezh2-PRC2 plays in regulating the fate of differentiating naïve CD4+ T cells. Loss of Ezh2 altered the expression of 1328 genes in Th0 and 1979 genes in iTreg cells. Gene expression changes were positively correlated in both cell types, indicating that Ezh2 targets similar genes in these cells. As expected, Ifng was one of the genes most increased in expression by following loss of Ezh2. In addition, expression of Tbx21 homolog Eomes, a transcription factor that regulates IFNG production, was also significantly increased. We then performed H3K27me3 ChIP-seq on Ezh2fl/fl and Ezh2fl/fl.CD4Cre Th0 cells. Consistent with cellular phenotype and RNA-seq data, we observed a loss of the H3K27me3 at Eomes, Il4 and Il10 loci . Very low levels of H3K27me3 marks were present at Ifng and Tbx21 loci in differentiated Ezh2fl/fl Th0 cells, suggesting that upon differentiation, upregulation or activation of transcription factors accounts for IFNG overproduction. A significant loss of H3K27me3 was observed >2kb upstream of Gata3 locus , however this did not result in increased transcription . Of the 22381 genes tested for changes in H3K27me3, 1360 showed a statistically significant decrease in Ezh2fl/fl.CD4Cre Th0 cells, compared to wildtype. Furthermore, 404 of these genes also showed a concomitant gain in expression in Ezh2fl/fl.CD4Cre Th0 cells, suggesting that these loci are likely direct Ezh2-PRC2 targets. Overall design: There are 3 biological replicates each of Ezh2fl/fl.CD4Cre and Ezh2fl/fl in both Th0 and iTreg cells for the RNA-seq experiment. There are 2 biological replicates each of Ezh2fl/fl.CD4Cre and Ezh2fl/fl in Th0 cells for the ChIP-seq experiment.
Publication Title
The polycomb repressive complex 2 governs life and death of peripheral T cells.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 10 Downloadable Samples
- IlluminaHiSeq2000
Description
T follicular helper (Tfh) cells are a subset of CD4+ T helper (Th) cells that migrate into germinal centers and promote B cell maturation into memory B and plasma cells. Tfh cells are necessary for promotion of protective humoral immunity following pathogen challenge, but when aberrantly regulated, drive pathogenic antibody formation in autoimmunity and undergo neoplastic transformation in angioimmunoblastic T-cell lymphoma and other primary cutaneous T-cell lymphomas. Limited information is available on the expression and regulation of genes in human Tfh cells. Using a fluorescence activated cell sorting-based strategy, we obtained primary Tfh and non-Tfh T effector (Teff) cells from tonsils and prepared genome-wide maps of active, intermediate, and poised enhancers determined by ChIP-seq, with parallel transcriptome analyses determined by RNA-seq. Tfh cell enhancers were enriched near genes highly expressed in lymphoid cells or involved in lymphoid cell function, with many mapping to sites previously associated with autoimmune disease in genome-wide association studies. A group of active enhancers unique to Tfh cells associated with differentially expressed genes was identified. Fragments from these regions directed expression in reporter gene assays. These data provide a significant resource for studies of T lymphocyte development and differentiation and normal and perturbed Tfh cell function. Overall design: Using a fluorescence activated cell sorting-based strategy, we obtained primary Tfh and non-Tfh T effector (Teff) cells from tonsils and prepared genome-wide maps of active, intermediate, and poised enhancers determined by ChIP-seq, with parallel transcriptome analyses determined by RNA-seq.
Publication Title
Global transcriptome analysis and enhancer landscape of human primary T follicular helper and T effector lymphocytes.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
EKLF is a Krppel-like transcription factor identified as a transcriptional activator and chromatin modifier in erythroid cells. EKLF-deficient (Eklf -/-) mice die at day 14.5 of gestation from severe anemia. In this study, we demonstrate that early progenitor cells fail to undergo terminal erythroid differention in Eklf -/- embryos. To discover potential EKLF target genes responsible for the failure of erythropoiesis, transcriptional profiling was performed with RNA from wild type and Eklf -/- early erythroid progenitor cells. These analyses identified significant perturbation of a network of genes involved in cell cycle regulation, with the critical regulator of the cell cycle, E2f2, at a hub. E2f2 mRNA and protein levels were markedly decreased in Eklf -/- early erythroid progenitor cells, which showed a delay in the G1-to-S-phase transition. Chromatin immunoprecipitation analysis demonstrated EKLF occupancy at the proximal E2f2 promoter in vivo. Consistent with the role of EKLF as a chromatin modifier, EKLF binding-sites in the E2f2 promoter were located in a region of EKLF-dependent DNase I sensitivity in early erythroid progenitor cells. We propose a model in which EKLF-dependent activation and modification of the E2f2 locus is required for cell cycle progression preceding terminal erythroid differentiation.
Publication Title
Failure of terminal erythroid differentiation in EKLF-deficient mice is associated with cell cycle perturbation and reduced expression of E2F2.
Sample Metadata Fields
Age, Specimen part
View Samples- Mus musculus
- 15 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Differentiation of muscle tissue is regulated by a complex network of transcription factors. The MEF2 family of transcription factors are important players in muscle development and differentiation.
Publication Title
MEF2 transcription factors regulate distinct gene programs in mammalian skeletal muscle differentiation.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 26 Downloadable Samples
- Illumina HiSeq 2000
Description
The production of definitive haematopoietic stem/progenitor cells from human pluripotent stem cells (hPSCs) remains a significant challenge. Using reporter lines to track the endothelial (SOX17) to haematopoietic (RUNX1C) transition, we found that hPSC differentiated in growth factor supplemented serum free medium generated RUNX1C+CD34+ clonogenic cells that homed to the bone marrow, but did not engraft. Compared to repopulation-competent cord blood CD34+ cells, RUNX1C+CD34+ progenitors lacked HOXA gene expression, indicating incorrect mesoderm patterning. This deficiency was ameliorated by a timed pulse of WNT activation combined with ACTIVIN antagonism. Significantly, these HOXA+ cultures now formed complex SOX17+ vessels that produced fetal liver-like haematopoietic cells, similar to the human aorta-gonad-mesonephros (AGM). Comparison of transcriptional profiles of these nascent haematopoietic stem/progenitors with cells isolated from human AGM confirmed significant similarities, consistent with the assignment of our in vitro generated cells to the definitive human haematopoietic lineage. Our findings argue that HOXA codes established early in differentiation predict cellular potential and provide correct cell patterning for the specification of definitive haematopoietic lineages from hPSCs. Overall design: mRNA profiles of 26 samples were obtained for 5 different cell populations and 2 different treatments.
Publication Title
Differentiation of human embryonic stem cells to HOXA<sup>+</sup> hemogenic vasculature that resembles the aorta-gonad-mesonephros.
Sample Metadata Fields
Treatment, Subject
View Samples- Mus musculus
- 4 Downloadable Samples
- Illumina Genome Analyzer IIx
Description
CTCF (CCCTC-binding factor) is a highly conserved 11-zinc finger DNA binding protein with tens of thousands of binding sites genome-wide. CTCF acts as a multifunctional regulator of transcription, having been previously associated with activator, repressor, and insulator activity. These diverse regulatory functions are crucial for preimplantation development and are implicated in the regulation of numerous lineage-specific genes. Despite playing a critical role in developmental gene regulation, the mechanisms that underlie developmental changes in CTCF recruitment and function are poorly understood. Our previous work suggested that differences in CTCF’s binding site sequence may affect the regulation of CTCF recruitment, as well as CTCF’s regulatory function. To investigate these two possibilities directly during a developmental process, changes in genome-wide CTCF binding and gene expression were characterized during in vitro differentiation of mouse embryonic stem cells. CTCF binding sites were initially separated into three classes (named LowOc, MedOc, and HighOc) based on similarity to the consensus motif. The LowOc class, with lower-similarity to the consensus motif, is more likely to show changes in binding during differentiation. These more dynamically bound sites are enriched for motifs that confer a lower in vitro affinity for CTCF, suggesting a mechanism where sites with low-binding affinity are more amenable to developmental control. Additionally, by comparing changes in CTCF binding with changes in gene expression during differentiation, we show that LowOc and HighOc sites are associated with distinct regulatory functions. In sum, these results suggest that the regulatory control of CTCF’s binding and function is dependent in part upon specific motifs within its DNA binding site. Overall design: Mouse E14 ES cells were differentiated in vitro for 4.5 days using retinoic acid. RNA-Seq was performed from cells collected before and after differentiation.
Publication Title
CTCF binding site sequence differences are associated with unique regulatory and functional trends during embryonic stem cell differentiation.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples