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SRP074063
Homo sapiens
12 Downloadable Samples
Illumina HiSeq 2000
Description
Targeting the Mdm2 oncoprotein by drugs has the potential of re-establishing p53 function and tumor suppression. However, Mdm2-antagonizing drug candidates, e. g. Nutlin-3a, often fail to abolish cancer cell growth sustainably. To overcome these limitations, we inhibited Mdm2 and simultaneously a second negative regulator of p53, the phosphatase Wip1/PPM1D. When combining Nutlin-3a with the Wip1 inhibitor GSK2830371 in the treatment of p53-proficient but not p53-deficient cells, we observed enhanced phosphorylation (Ser 15) and acetylation (Lys 382) of p53, increased expression of p53 target gene products, and synergistic inhibition of cell proliferation. Surprisingly, when testing the two compounds individually, largely distinct sets of genes were induced, as revealed by deep sequencing analysis of RNA. In contrast, the combination of both drugs led to an expression signature that largely comprised that of Nutlin-3a alone. Moreover, the combination of drugs, or the combination of Nutlin-3a with Wip1-depletion by siRNA, activated p53-responsive genes to a greater extent than either of the compounds alone. Simultaneous inhibition of Mdm2 and Wip1 enhanced cell senescence and G2/M accumulation. Taken together, the inhibition of Wip1 might fortify p53-mediated tumor suppression by Mdm2 antagonists. Overall design: Expression profiling by high throughput sequencing
Publication Title
Cooperation of Nutlin-3a and a Wip1 inhibitor to induce p53 activity.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina HiSeq 2000
Description
Endogenous pancreatic multipotent progenitors (PMPs) are ideal candidates for regenerative approaches to compensate for b-cell loss since their b-cell–producing capacities as well as strategic location would eliminate unnecessary invasive manipulations. However, little is known about the status and potentials of PMPs under diabetic conditions. Here we show that b-cell metabolic stress and hyperglycemia enhance the proliferation capacities of adult PMP cells and bias their production of progeny toward b-cells in mouse and human. These effects are dynamic and correlate with functional b-cell regeneration when conditions allow. Overall design: Insulin-positive Glut2-low cell population of adult pancreatic tissue is enriched for PMP cells. Streptozocin (STZ) can enter beta-cells via Glut2 , induce cell death and consequently diabetes. Insulin-positive cells from two groups (STZ-injected experiment and vehicle-injected control, n=3/group) of MIP-GFP transgenic male mice were sorted to Glut2-low (Glut2L) and Glut2-high (Glut2H) by FACS. Total RNA from these samples were extracted for transcriptome analysis.
Publication Title
Diabetes enhances the proliferation of adult pancreatic multipotent progenitor cells and biases their differentiation to more β-cell production.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 5 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The 24R,25-dihydroxyvitamin D metabolite (24R,25D) has long been suspected of participating to bone fracture repair. We used Cyp24a1-deficient mice, unable to produce 24R25D, to observe gene expression in callus tissue compared to that of control littermates.
Publication Title
Optimal bone fracture repair requires 24R,25-dihydroxyvitamin D3 and its effector molecule FAM57B2.
Sample Metadata Fields
Age, Specimen part, Treatment, Time
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
Combined chromatin and expression analysis reveals specific regulatory mechanisms within cytokine genes in the macrophage early immune response.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
Macrophages play a critical role in innate immunity, and the expression of early response genes orchestrate much of the initial response of the immune system. Macrophages undergo extensive transcriptional reprogramming in response to inflammatory stimuli such as Lipopolysaccharide (LPS). To identify gene transcription regulation patterns involved in early innate immune responses, we used two genome-wide approaches - gene expression profiling and chromatin immunoprecipitation-sequencing (ChIP-seq) analysis. We examined the effect of 2 hrs LPS stimulation on early gene expression and its relation to chromatin remodeling (H3 acetylation; H3Ac) and promoter binding of Sp1 and RNA polymerase II phosphorylated at serine 5 (S5P RNAPII), which is a marker for transcriptional initiation. Our results indicate novel and alternative gene regulatory mechanisms for certain proinflammatory genes. We identified two groups of up-regulated inflammatory genes with respect to chromatin modification and promoter features. One group, including highly up-regulated genes such as tumor necrosis factor (TNF), was characterized by H3Ac, high CpG content and lack of TATA boxes. The second group, containing inflammatory mediators (interleukins and CCL chemokines), was up-regulated upon LPS stimulation despite lacking H3Ac in their annotated promoters, which were low in CpG content but did contain TATA boxes. Genome-wide analysis showed that few H3Ac peaks were unique to either +/-LPS condition. However, within these, an unpacking/expansion of already existing H3Ac peaks was observed upon LPS stimulation. In contrast, a significant proportion of S5P RNAPII peaks (approx 40%) was unique to either condition. Furthermore, data indicated a large portion of previously unannotated TSSs, particularly in LPS-stimulated macrophages, where only 28% of unique S5P RNAPII peaks overlap annotated promoters. The regulation of the inflammatory response appears to occur in a very specific manner at the chromatin level for specific genes and this study highlights the level of fine-tuning that occurs in the immune response.
Publication Title
Combined chromatin and expression analysis reveals specific regulatory mechanisms within cytokine genes in the macrophage early immune response.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 24 Downloadable Samples
- Illumina HiSeq 2000
Description
We examined transcriptome-wide effects of 4SC-202 in L3.6, BXPC3 and PANC1 cells as well as its effect on TGFß signaling Overall design: We performed mRNA sequencing from L3.6, BXPC3 and PANC1 cells following following DMSO, 4SC-202 and/or TGFß treatment. The mRNA-Seq includes following conditions: 4SC-202 vs DMSO (for L3.6, BXPC3 and PANC1 cells), TGFß vs DMSO and 4SC-202+TGFß vs TGFß (for PANC1 cells). The libraries were performed in triplicates.
Publication Title
Histone deacetylase class-I inhibition promotes epithelial gene expression in pancreatic cancer cells in a BRD4- and MYC-dependent manner.
Sample Metadata Fields
Cell line, Subject
View Samples- Homo sapiens
- 21 Downloadable Samples
- Illumina HiSeq 2000
Description
We examined context specific function of BRD4 in promoting lineage specific gene expression and show that BRD4 is essential for osteoblast differentiation. Overall design: We performed mRNA sequencing from hFOB cells (undifferentiated and differentiated for 5 days into osteoblastic lineage) following BRD4 inhibition by JQ1 or siRNA mediated depletion. The mRNA-Seq includes namely 7 conditions: undifferentiated hFOBs treated with DMSO or non-targeting control siRNA (siCNTR), differentiated hFOBs with DMSO or siCNTR treatments; differentiated hFOBs treated with JQ1 or two siRNAs against BRD4 (#3 & #4). The libraries were performed in triplicates.
Publication Title
BRD4 localization to lineage-specific enhancers is associated with a distinct transcription factor repertoire.
Sample Metadata Fields
Specimen part, Treatment, Subject
View Samples- Homo sapiens
- 18 Downloadable Samples
- Affymetrix Human Genome U133A 2.0 Array (hgu133a2)
Description
Tacrolimus and Sirolimus are commonly used to maintain immunosuppression in kidney transplantation. However, their effects on immune cells and allograft molecular profiles have not been elucidated.
Publication Title
Cellular and molecular immune profiles in renal transplant recipients after conversion from tacrolimus to sirolimus.
Sample Metadata Fields
Specimen part, Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Human skin-derived precursor cells (hSKP) are a stem cell population that represents key candidates for cell based-therapy. Inflammation, however, is often present in situations where cellular replacement therapy is required. These inflammatory conditions, and more specifically the presence of the cytokine interferon (IFN)-, might result in an increase of MHC class II antigens in hSKP-derived grafts and facilitate their rejection.
Publication Title
Human skin-derived precursor cells are poorly immunogenic and modulate the allogeneic immune response.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Mus musculus
- 7 Downloadable Samples
- Illumina HiSeq 2000
Description
The Mdm2 oncoprotein ubiquitinates and antagonizes p53 but may also carry out p53-independent functions. Here we report that Mdm2 is required for the efficient generation of induced pluripotent stem cells (iPSCs) from murine embryonic fibroblasts, in the absence of p53. Similarly, Mdm2 depletion in the context of p53 deficiency also promoted the differentiation of human mesenchymal stem cells and diminished clonogenic survival of cancer cells. Most of the Mdm2-controlled genes also responded to the inactivation of the Polycomb Repressor Complex 2 (PRC2) and its catalytic component EZH2. Mdm2 physically associated with EZH2 on chromatin, enhancing the trimethylation of Histone 3 at lysine 27 and the ubiquitination of Histone 2A at lysine 119 (H2AK119) at its target genes. Removing Mdm2 simultaneously with the H2AK119 E3 ligase Ring1B/RNF2 further induced these genes and synthetically arrested cell proliferation. In conclusion, Mdm2 supports the Polycomb-mediated repression of lineage specific genes independent of p53. Overall design: Expression profiling by high throughput sequencing of p53 ko MEFs, p53Mdm2 ko MEFs, p53ko Mdm2 C462A ki MEFs.
Publication Title
MDM2 Associates with Polycomb Repressor Complex 2 and Enhances Stemness-Promoting Chromatin Modifications Independent of p53.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples