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GSE43010
Homo sapiens
40 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The identification of recurrent somatic mutations in genes encoding epigenetic enzymes, coupled with biochemical studies demonstrating aberrant recruitment of epigenetic enzymes such as histone deacetylases (HDACs) and histone methyltransferases (HMTs) to promoter regions through association with oncogenic fusion proteins such as PML-RAR and AML1-ETO has provided a strong rationale for the development compounds that target the epigenome for the treatment of cancer. HDAC inhibitors (HDACi) are potent inducers of tumor cell apoptosis but it remains unclear why tumor cells are selectively sensitive to HDACi-induced cell death.
Publication Title
HDAC inhibitors induce tumor-cell-selective pro-apoptotic transcriptional responses.
Sample Metadata Fields
Specimen part, Time
View Samples- Mus musculus
- 4 Downloadable Samples
Illumina HiSeq 2000
Description
Targeting BET bromodomain proteins utilizing small molecules in an emerging anti-cancer strategy with clinical evaluation of at least six inhibitors now underway. While MYC downregulation was initially proposed as a key mechanistic property of BET inhibitors, recent evidence suggests that additional anti-tumor activities are important. Using the Eµ-Myc model of B-cell lymphoma we demonstrate that BET inhibition with JQ1 is a potent inducer of p53-independent apoptosis that occurs in the absence of effects on Myc gene expression. JQ1 skews the expression of pro-apoptotic (Bim) and anti-apoptotic (BCL-2/BCL-xL) BCL-2 family members to directly engage the mitochondrial apoptotic pathway. Consistent with this, Bim knockout or Bcl-2 overexpression inhibited apoptosis induction by JQ1. We identified lymphomas that were either intrinsically resistant to JQ1-mediated death or acquired resistance following in vivo exposure. Strikingly, in both instances BCL-2 was strongly upregulated and was concomitant with activation of RAS pathways. Eµ-Myc lymphomas engineered to express activated Nras upregulated BCL-2 and acquired a JQ1-resistance phenotype. These studies provide important information on mechanisms apoptosis induction and resistance to BET-inhibition, while providing further rationale for the translation of BET inhibitors in aggressive B-cell lymphomas. Overall design: RNA-Sequencing of JQ1 resistant and sensitive Eµ-Myc cell lines
Publication Title
BET Inhibition Induces Apoptosis in Aggressive B-Cell Lymphoma via Epigenetic Regulation of BCL-2 Family Members.
Sample Metadata Fields
Cell line, Subject
View Samples- Mus musculus
- 8 Downloadable Samples
- Illumina HiSeq 2500
Description
BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We discovered that the maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and IFN-? induced CD274 expression across different human and mouse tumor cell lines and primary patient samples. Mechanistically, BETi decreased Brd4 occupancy at the Cd274 locus without any change in Myc occupancy, resulting in transcriptional pausing and rapid loss of Cd274 mRNA production. Finally, targeted inhibition of the PD1/PD-L1 axis by combining anti-PD1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncovers a novel interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provides novel insight into the transcriptional regulation of CD274. Overall design: RNA Sequencing of Eµ-Myc lymphoma cell lines treated for 2 hours with JQ1, or DMSO vehicle.
Publication Title
BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1.
Sample Metadata Fields
Cell line, Treatment, Subject
View Samples- Mus musculus
- 57 Downloadable Samples
- Illumina HiSeq 4000
Description
Whole blood RNA-seq was leveraged to explore gene expression changes induced in mice 24 hours after immunisation with a second dose of a licensed vaccine against capsular group B meningococcus, one of the vaccines components, or one of several comparator groups. Overall design: mRNA was profiled from RNA extracted from mouse whole blood, 5-6 samples per group, using an Illumina HiSeq4000
Publication Title
Comparative transcriptomics between species attributes reactogenicity pathways induced by the capsular group B meningococcal vaccine, 4CMenB, to the membrane-bound endotoxin of its outer membrane vesicle component.
Sample Metadata Fields
Sex, Cell line, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
We used a RAG2-GFP reporter mouse to show that RAG+ B lineage cells can be found in the small intestinal lamina proria in normally-housed mice at weaning age. We used microarry expression analysis to compare the RAG2+ population in the gut to the RAG2+ B lineage population in the bone marrow.
Publication Title
Microbial colonization influences early B-lineage development in the gut lamina propria.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 78 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
We used microarrays to detail the global programme of gene expression underlying the disease progression in the mutant mice compared to their control littermates.
Publication Title
Microarray expression analysis and identification of serum biomarkers for Niemann-Pick disease, type C1.
Sample Metadata Fields
Sex, Specimen part, Treatment
View Samples- Homo sapiens
- 48 Downloadable Samples
- Affymetrix Human Exon 1.0 ST Array [transcript (gene) version (huex10st)
Description
7-dehydrocholesterol reductase catalyzes the reduction of 7-dehydrocholesterol to cholesterol. In Smith-Lemli-Opitz syndrome, mutations in DHCR7 prevents this conversion. We have found iPS cells derived from SLOS patients exhibit accelerated differentiation under cholesterol poor conditions.
Publication Title
Modeling Smith-Lemli-Opitz syndrome with induced pluripotent stem cells reveals a causal role for Wnt/β-catenin defects in neuronal cholesterol synthesis phenotypes.
Sample Metadata Fields
Specimen part, Cell line, Time
View Samples- Homo sapiens
- 142 Downloadable Samples
- Illumina humanRef-8 v2.0 expression beadchip
Description
Correlates of immune mediated protection to most viral and cancer vaccines are still unknown. This impedes the development of novel vaccines to incurable diseases such as HIV and cancer. In this study, we have used functional genomics and polychromatic flow cytometry to define the signature of the immune response to the yellow fever (YF) vaccine 17D (YF17D) in a cohort of forty volunteers followed for up to one year after vaccination. We show that immunization with YF17D leads to an integrated immune response that includes several effector arms of innate immunity including complement, the inflammasome and interferons, as well as adaptive immunity as shown by an early T cell response followed by a brisk and variable B cell response. Development of these responses is preceded, as demonstrated in three independent vaccination trials and in a novel in vitro system of primary immune responses (Modular IMmune In vitro Construct (MIMIC) system), by the coordinated up-regulation of transcripts for specific transcription factors including STAT1, IRF7 and ETS2 that are upstream of the different effector arms of the immune response. These results clearly show that the immune response to a strong vaccine is preceded by coordinated induction of masters transcription factors, that lead to the development of a broad, polyfunctional and persistent immune response that integrates all effector cells of the immune system.
Publication Title
Yellow fever vaccine induces integrated multilineage and polyfunctional immune responses.
Sample Metadata Fields
No sample metadata fields
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