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GSE6263
Homo sapiens
5 Downloadable Samples
Affymetrix Human Genome U133A Array (hgu133a)
Description
In an effort to identify genes whose expression is regulated by activated PI3K signaling, we performed microarray analysis and subsequent qRT-PCR on an isogenic set of PTEN gene-targeted human cancer cells. Numerous p53 effectors were upregulated following PTEN deletion, including p21, GDF15, PIG3, NOXA, and PLK2. Stable depletion of p53 led to reversion of the gene expression program. Western blots revealed that p53 was stabilized in HCT116 PTEN-/- cells via an Akt1-dependent and p14ARF-independent mechanism. Stable depletion of PTEN in untransformed human fibroblasts and epithelial cells also led to upregulation of p53 and senescent-like growth arrest. Simultaneous depletion of p53 rescued this phenotype, enabling PTEN-depleted cells to continue proliferating. Next, we tested whether oncogenic PIK3CA, like inactivated PTEN, could activate p53. Retroviral expression of oncogenic human PIK3CA in MCF10A cells led to activation of p53 and upregulation of p53-regulated genes. Stable depletion of p53 reversed these PIK3CA-induced expression changes and synergized with oncogenic PIK3CA in inducing anchorage-independent growth. Finally, targeted deletion of an endogenous allele of oncogenic but not wild-type PIK3CA in a human cancer cell line led to a reduction in p53 levels and a decrease in the expression of p53-regulated genes. These studies demonstrate that activation of PI3K signaling by mutations in PTEN or PIK3CA can lead to activation of p53-mediated growth suppression in human cells, indicating that p53 can function as a brake on PIP3-induced mitogenesis during human cancer pathogenesis.
Publication Title
Activation of p53-dependent growth suppression in human cells by mutations in PTEN or PIK3CA.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 25 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
The initiation of the mucosal immune response in Peyers patch (PP) relies on the sampling, processing and efficient presentation of foreign antigens by dendritic cells (DC). PP DC encompass five subsets, among which CD11b+ conventional DC (cDC) and LysoDC have distinct progenitors and functions but share many cell surface markers. This has previously led to confusion between these two subsets. In addition, another PP DC subset, termed double-negative (DN), remains poorly characterized. Here, we have studied the genetic relatedness of the different subsets of PP cDC at steady state and under TLR7 ligand stimulation. We also provide the transcriptional profiles of subepithelial TIM-4- and interfollicular TIM-4+ macrophages.
Publication Title
Distribution, location, and transcriptional profile of Peyer's patch conventional DC subsets at steady state and under TLR7 ligand stimulation.
Sample Metadata Fields
Sex, Age, Specimen part, Treatment
View Samples- Mus musculus
- 13 Downloadable Samples
Illumina HiSeq 2500
Description
The specification of hematopoietic cells in the developing embryo occurs in specific stages and is regulated by the successive establishment of specific transcriptional networks. However, the molecular mechanisms of how the different stages switch from one to another are still not well understood. Hematopoietic cells arise from endothelial cells within the dorsal aorta which transit into hematopoietic cells by a process called the endothelial-hematopoietic transition (EHT) which does not involve DNA replication. The transcription factor RUNX1 is essential for this process. Using the differentiation of mouse embryonic stem cells carrying an inducible version of RUNX1, we have previously shown that hematopoietic genes are primed prior to the EHT by the binding of transcription factors required to form both endothelial and hematopoietic cells (FLI-1 and SCL/TAL1). We demonstrated that after induction RUNX1 reshapes the transcription factor binding landscape by causing a relocation of these factors and pulling them towards its binding sites. In the study presented here, we employed the same system to globally dissect the transcriptional processes that underlay the EHT. We demonstrate that the RUNX1-mediated movement of FLI-1 involves the recruitment of the basal transcription components CDK9 and BRD4 to promoters. The looping factor LDB1 to binds to distal elements and after induction relocates towards RUNX1/FLI-1 to form a co-localizing complex in chromatin. This entire process is blocked by treatment with the BRD4 inhibitor JQ1. Our study constitutes a paradigm for transcriptional processes driving transitions in cellular shape and function which are widely observed in development and disease. Overall design: RNA-seq expreiments have been used to study RUNX1 transcription factor during Hematopoietic specification
Publication Title
The Co-operation of RUNX1 with LDB1, CDK9 and BRD4 Drives Transcription Factor Complex Relocation During Haematopoietic Specification.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 30 Downloadable Samples
- NextSeq 500
Description
Development requires the cooperation of tissue-specific and ubiquitously expressed transcription factors, such as Sp-family members. However, the molecular details of how ubiquitous factors participate in developmental processes are still unclear. We previously showed that during the differentiation of embryonic stem cells lacking Sp1 DNA binding activity (Sp1deltaDBD/deltaDBD cells), early blood progenitors are formed. However, gene expression during differentiation becomes progressively deregulated and terminal differentiation is severely compromised. Here we studied the cooperation of Sp1 and its closest paralogue Sp3 in hematopoietic development and demonstrate that Sp1 and Sp3 binding sites largely overlap. Sp3 cooperates with Sp1deltaDBD/deltaDBD but is unable to support hematopoiesis in the complete absence of Sp1. Using single cell gene expression analysis, we show that the lack of Sp1 DNA binding leads to a distortion of cell fate decision timing, indicating that stable chromatin bi nding of Sp1 is required to maintain robust differentiation trajectories. Overall design: RNA-Seq in ESC, Flk, HE1, HE2 and progenitor cells with WT, Sp1deltaDBD or Sp3KO
Publication Title
Robust hematopoietic specification requires the ubiquitous Sp1 and Sp3 transcription factors.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 10 Downloadable Samples
- NextSeq 500
Description
Long terminal repeat (LTR) elements are wide-spread in the human genome and have the potential to act as promoters and enhancers. Their expression is therefore under tight epigenetic control. We previously reported that a member of the THE1B class of LTR elements in classical Hodgkin Lymphoma (cHL) acted as a promoter for the growth factor receptor gene CSF1R and that expression of this gene is required for tumor survival. However, to which extent and how such elements participate in globally shaping the unique cHL gene expression program is unknown. To address this question we mapped the genome-wide activation of THE1-LTRs in cHL cells using a targeted next generation sequencing approach (RACE-Seq). Integration of these data with global gene expression data from cHL and control B cell lines showed a unique pattern of LTR activation impacting on gene expression, including genes associated with the cHL phenotype. We also show that global LTR activation is induced by strong inflammatory stimuli. Together these results demonstrate that LTR activation provides an additional layer of gene deregulation in classical Hodgkin lymphoma and highlight the potential impact of genome-wide LTR activation in other inflammatory diseases. Overall design: RNA-Seq in laser capture microdissected (LCM) tumour (TU) and non tumour cells (NTC) primary HL material from patient samples
Publication Title
Global long terminal repeat activation participates in establishing the unique gene expression programme of classical Hodgkin lymphoma.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 2 Downloadable Samples
- NextSeq 500
Description
Development requires the cooperation of tissue-specifically and ubiquitously expressed transcription factors, such as Sp-family members. However, the molecular details of how ubiquitous factors participate in developmental processes are still unclear. We previously showed that during the differentiation of embryonic stem cells lacking Sp1 DNA binding activity (Sp1DDBD/DDBD cells), early blood progenitors are formed. However, gene expression during differentiation becomes progressively deregulated and terminal differentiation is blocked. Here we studied the cooperation of Sp1 and its homologue Sp3 in hematopoietic development and demonstrate that Sp1 and Sp3 binding sites largely overlap. Sp3 cooperates with Sp1DDBD/DDBD cells but is unable to support hematopoiesis in the complete absence of Sp1. Using single cell gene expression analysis, we show that the lack of Sp1 DNA binding leads to a distortion of cell fate decision timing, indicating that stable chromatin binding of Sp1 is required to maintain robust differentiation trajectories. Overall design: Chromium 10X - Single-cell RNA-seq of Sp1 wild-type and Sp1 DNA binding domain mutant cells
Publication Title
Robust hematopoietic specification requires the ubiquitous Sp1 and Sp3 transcription factors.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 49 Downloadable Samples
- Affymetrix HT HG-U133+ PM Array Plate (hthgu133pluspm)
Description
There is a controversy surrounding the existence of palmoplantar pustulosis (PPP) and palmoplantar pustular psoriasis (PPPP) as separate clinical entities or as variants of the same clinical entity. We used gene expression microarray to compare gene expression in PPP and PPPP. PPP and PPPP could not be differentiated using gene expression microarray suggesting that they are not distinct clinical entities. Increased expression of GPRIN1, and ADAM23 in keratinocytes suggests that these proteins could be new therapeutic targets for PPP/PPPP.
Publication Title
Based on Molecular Profiling of Gene Expression, Palmoplantar Pustulosis and Palmoplantar Pustular Psoriasis Are Highly Related Diseases that Appear to Be Distinct from Psoriasis Vulgaris.
Sample Metadata Fields
Specimen part, Disease, Subject
View Samples- Homo sapiens
- 20 Downloadable Samples
- Illumina HiSeq 2500
Description
RUNX1 is a frequent target of translocations in acute myeloid leukemia whereby its DNA binding domain fuses to different epigenetic regulators. To assess how different RUNX1 fusion proteins interact with the epigenome we compared the global binding patterns and the chromatin landscape of t(8;21) and t(3;21) AML which express RUNX1-ETO and RUNX1-EVI-1, respectively. We found that differential prognosis for these types of AML is reflected in fundamental differences in gene expression, chromatin landscape, binding patterns of the fusion proteins and other transcription factors as identified by genome-wide digital footprinting in patients. As previously shown for RUNX1-ETO, knockdown of RUNX1-EVI-1 expression initiates differentiation of t(3;21) cells which is associated with up-regulation of genes vital for myeloid differentiation, including C/EBPa. Furthermore, by expressing either dominant-negative C/EBP or an inducible C/EBPa construct in t(3;21) cells we show that C/EBPa is necessary and sufficient for the differentiation response of these cells to RUNX1-EVI-1 knockdown. Overall design: RNA-seq expreiments have been used to study the chromatin landscape of t(8;21) and t(3;21) AML
Publication Title
RUNX1-ETO and RUNX1-EVI1 Differentially Reprogram the Chromatin Landscape in t(8;21) and t(3;21) AML.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 67 Downloadable Samples
- Affymetrix Human Genome U219 Array (hgu219)
Description
Parkinsons Disease is a multi-system, disabling progressive neurodegenerative condition. Clinical progression is highly heterogeneous and, thus far, there are not available biomarkers to accurately predict the rate of disease progression. Thus, identifying molecular signatures that allow discriminating between different progression rates might significantly assist the therapeutic strategy, and enable improved outcomes in clinical trials.
Publication Title
Gene Expression Differences in Peripheral Blood of Parkinson's Disease Patients with Distinct Progression Profiles.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 20 Downloadable Samples
- IlluminaHiSeq1000
Description
Transcriptome analysis by RNAseq of leukemia model promoted by MLL-Af4 or MLL-AF9 fusion proteins. We find each fusion protein promotes a specific gene signature correlating to those identified in patients Overall design: Human CD34+ hematopoietic stem and progenitor cells were transduced with retrovirus expressing MLL-Af4 or MLL-AF9. Transduced cells were transplanted into immunodeficient mice to induce lymphoid leukemia or placed in myeloid in vitro culture. CD19+ lymphoid leukemia cells (3 AF9, 6 Af4), control health CD19+CD34+ proB cells (n=3) and 4 pairs of Af4 and AF9 CD33+CD19- myeloid culture cells were collected for RNA-seq
Publication Title
Instructive Role of MLL-Fusion Proteins Revealed by a Model of t(4;11) Pro-B Acute Lymphoblastic Leukemia.
Sample Metadata Fields
No sample metadata fields
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