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GSE67388
Mus musculus
18 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Somatic mutations of the MLL2 methyltransferase gene represent a common genetic lesion in multiple cancer types. In diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) (collectively, over 70% of all lymphoma diagnoses), these mutations are highly recurrent and appear early during transformation, possibly in pre-malignant precursors. Here we show that FL- and DLBCL-associated MLL2 mutations impair its enzymatic activity and lead to diminished global H3K4 methylation in normal germinal-center (GC) B cells and DLBCL, consistent with the enrichment of MLL2 binding at enhancer and promoter regions marked by mono- and tri-methylation. Conditional deletion of Mll2 early during B cell development, but not after initiation of the GC reaction, leads to increased percentages and numbers of GC B cells, which feature a distinct transcriptional profile defined by the enrichment of cell-cycle regulatory and B-cell receptor signaling genes. Consistently, Mll2-deficient B cells exhibit proliferative advantage and accumulation in the S phase of the cell cycle, which is influenced by the number of cell divisions. While GC-specific loss of Mll2 was not sufficient to initiate malignant transformation, compound Mll2-deficient/BCL2-transgenic mice displayed an increased incidence of clonal lymphoproliferations resembling the features of human FL and DLBCL. These findings suggest that early MLL2 loss favors BCL2-induced lymphomagenesis by remodeling the epigenetic landscape of the cancer precursor cells. Eradication of MLL2-deficient cells may represent a rational therapeutic approach targeting early tumorigenic events.
Publication Title
Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis.
Sample Metadata Fields
Sex, Specimen part
View Samples- Mus musculus
- 14 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Inactivating mutations of the gene encoding for the CREBBP acetyltransferase are highly frequent in diffuse large B cell lymphoma (DLBCL, 30% of cases) and follicular lymphoma (FL, 60% of cases), the two most common cancers derived from thegerminal-center (GC). However, the role of CREBBP inactivation in lymphomagenesisremains unclear. Using functional epigenomics and mouse genetics, here we definethe program modulated by CREBBP in primary human GC B cells and show thatCREBBP regulates enhancer/super-enhancer networks, with specific roles in GC/post-GC cell fate decisions. Conditional GC-specific deletion of Crebbp in the mouseperturbs the expression of a limited set of genes involved in the regulation of signaltransduction (BCR, TLR and CD40), lineage specification (NF-B and BCL6) andterminal B cell differentiation (PRDM1, IRF4). Consistently, Crebbp-deficient B cellsexhibit proliferative advantage and show impaired plasma cell differentiation. WhileGC-specific loss of Crebbp was not sufficient to initiate malignant transformation,compound Crebbp-haploinsufficient/BCL2-transgenic mice, mimicking the genetics ofFL and DLBCL, display an increased incidence of clonal lymphoid malignanciesrecapitulating the features of the human diseases. These findings establish CREBBPas a haploinsufficient tumor suppressor gene in GC B cells and provide insights intothe mechanisms and targes by which loss of CREBBP contributes to lymphomagenesis.
Publication Title
The CREBBP Acetyltransferase Is a Haploinsufficient Tumor Suppressor in B-cell Lymphoma.
Sample Metadata Fields
Sex, Specimen part
View Samples- Homo sapiens
- 162 Downloadable Samples
- Illumina HumanHT-12 V4.0 expression beadchip
Description
Paradoxical cryptococcosis-associated immune reconstitution inflammatory syndrome
Publication Title
Transcriptomic Predictors of Paradoxical Cryptococcosis-Associated Immune Reconstitution Inflammatory Syndrome.
Sample Metadata Fields
Specimen part
View Samples- Mus musculus
- 46 Downloadable Samples
- Affymetrix Murine Genome U74A Version 2 Array (mgu74av2)
Description
We utilized oligonucleotide microarrays to measure cellular mRNA decay rates in mock- or reovirus-infected murine L929 cells to determine if changes in host mRNA expression are a consequence of reovirus-induced alterations in cellular mRNA stability.
Publication Title
Reovirus infection induces stabilization and up-regulation of cellular transcripts that encode regulators of TGF-β signaling.
Sample Metadata Fields
Cell line, Time
View Samples- Homo sapiens
- 6 Downloadable Samples
Description
Numerous mammalian proto-oncogene and other growth-regulatory transcripts are upregulated in malignancy due to abnormal mRNA stabilization. In hepatoma cells expressing a hepatitis C virus (HCV) subgenomic replicon, we found that the viral nonstructural protein 5A (NS5A), a protein known to bind to viral RNA, also bound specifically to human cellular transcripts that encode regulators of cell growth and apoptosis, and this binding correlated with transcript stabilization. An important subset of human NS5A-target transcripts contained GU-rich elements, sequences known to destabilize mRNA. We found that NS5A bound to GU-rich elements in vitro and in cells. Mutation of the NS5A zinc finger abrogated its GU-rich element-binding and mRNA stabilizing activities. Overall, we identified a molecular mechanism whereby HCV manipulates host gene expression by stabilizing host transcripts in a manner that would promote growth and prevent death of virus-infected cells, allowing the virus to establish chronic infection and lead to the development of hepatocellular carcinoma. Overall design: Calculate mRNA decay rate by examining RNA-seq expression levels of 2 samples (Huh and Huh-HCV) at 3 time points (0h, 3h, and 6h) after transcription arrest. RNA-IP followed by RNA-seq on 2 samples (Huh and Huh-HCV).
Publication Title
The hepatitis C viral nonstructural protein 5A stabilizes growth-regulatory human transcripts.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 22 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Activation of Sirtuin (silent mating type information regulation 2 homolog) 1, or SIRT1, is an unexplored therapeutic approach for treatment of inflammatory diseases. The goal of this study was to evaluate the clinical activity and tolerability of multiple doses of SRT2104, a selective activator of SIRT1, in patients with moderate to severe psoriasis after day 84 of treatment. Forty patients were randomized 4:1 to three escalating doses of SRT2104 (250, 500, 1000 mg/d SRT2104 or placebo). Across all SRT2104 groups, 34.6% of patients (9 out of 26; 90% CI 18.0%-54.2%, p<0.0001) achieved good to excellent histological improvement based on skin biopsies taken at baseline and day 84. To evaluate the changes in expression profile with treatment and to identify pathways involved in histological improvement, a subset of 22 Pre and Post treatment biopsies from 11 patients (4 Placebo, 7 Active Treatment) were hybridized to hgu133plus2 chips. Improvement in histology was associated with modulation of IL-17 and TNF-_ signaling pathways and keratinocyte differentiation target genes. Various studies suggest a crucial role of TNF_ and IL-17 in psoriasis pathogenesis and IL-17/TNF_ synergism induces a strong induction of differentially expressed genes in psoriasis, thus advocating a crucial role of IL-17/TNF_ combination in the molecular basis of disease (Chiricozzi et al., 2010). In the current study, broad scale gene expression profiling revealed that SRT2104 significantly reduced known IL-17 and TNF_ responsive genes including SERPINB4, S100A12, SERPINB3, kynu etc. even though the sample size for this analysis was small. One of the most highly modulated genes by SRT2104 included Kynu, a gene that regulates tryptophan metabolism, known to confer antibacterial effector functions (Daubener and MacKenzie, 1999). Interestingly kynu is part of the etanercept residual genomic profile that is not modulated by etanercept therapy even though clinical efficacy is achieved. Possibly, SRT2104 may be modulating the lipid barrier of the epidermis of psoriatic skin via modulation of keratinocyte diferentiation genes, which would be consistent with the observed improvement in skin histology. These results indicate a combinatorial effect of SRT2104 on TNF_, and IL-17 inflammatory signaling pathways and keratinocyte differentiation that could be a contributing factor towards improvement in clinical scores by the SIRT1 activator, SRT2104.
Publication Title
A Randomized, Placebo-Controlled Study of SRT2104, a SIRT1 Activator, in Patients with Moderate to Severe Psoriasis.
Sample Metadata Fields
Treatment, Subject, Time
View Samples- Homo sapiens
- 1 Downloadable Sample
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
The Bromo-domain and PHD-finger protein, BRPF3, forms a complex with HBO1 and regulates the initiation of DNA replication. BRPF3-dependent histone H3K14 enriched in chromatin surrounding a fraction of replication origins may play an important role in origin firing.
Publication Title
BRPF3-HBO1 regulates replication origin activation and histone H3K14 acetylation.
Sample Metadata Fields
Cell line, Treatment
View Samples- Mus musculus
- 20 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The goal of the study is a high-throughput evaluation of the effect of TGFb treatment on gene expression.
Publication Title
Resolving the Combinatorial Complexity of Smad Protein Complex Formation and Its Link to Gene Expression.
Sample Metadata Fields
Specimen part
View Samples- Xenopus laevis
- 4 Downloadable Samples
- Affymetrix Xenopus laevis Genome 2.0 Array (xlaevis2)
Description
Analysis of epithelial explants injected with the intracellular domain of Notch (ICD) to block the formation of multi-ciliate and proton secreting cells or with dominant negative human Mastermind (HMM) or a DNA binding mutant of Mastermind (DBM) to induce the formation of ectopic multi-ciliate and proton secreting cells. Results show which genes are up or down-regulated when DBM/HMM are compared to ICD.
Publication Title
Multicilin promotes centriole assembly and ciliogenesis during multiciliate cell differentiation.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 16 Downloadable Samples
- IlluminaHiSeq2000
Description
Many thousand long non-coding (lnc) RNAs are mapped in the human genome. Time consuming studies using reverse genetic approaches by post-transcriptional knock-down or genetic modification of the locus demonstrated diverse biological functions for a few of these transcripts. The Human Gene Trap Mutant Collection in haploid KBM7 cells is a ready-to-use tool for studying protein-coding gene function. As lncRNAs show remarkable differences in RNA biology compared to protein-coding genes, it is unclear if this gene trap collection is useful for functional analysis of lncRNAs. Here we use the uncharacterized LOC100288798 lncRNA as a model to answer this question. Using public RNA-seq data we show that LOC100288798 is ubiquitously expressed, but inefficiently spliced. The minor spliced LOC100288798 isoforms are exported to the cytoplasm, whereas the major unspliced isoform is nuclear localized. This shows that LOC100288798 RNA biology differs markedly from typical mRNAs. De novo assembly from RNA-seq data suggests that LOC100288798 extends 289kb beyond its annotated 3'' end and overlaps the downstream SLC38A4 gene. Three cell lines with independent gene trap insertions in LOC100288798 were available from the KBM7 gene trap collection. RT-qPCR and RNA-seq confirmed successful lncRNA truncation and its extended length. Expression analysis from RNA-seq data shows significant deregulation of 41 protein-coding genes upon LOC100288798 truncation. Our data shows that gene trap collections in human haploid cell lines are useful tools to study lncRNAs, and identifies the previously uncharacterized LOC100288798 as a potential gene regulator. Overall design: We cultured and processed 8 KBM7 cell lines in one batch. These cell lines were: two wild type KBM7 cells (WT2 and WT3), two monoclonal KBM7 cell lines with gene trap cassette insertions outside of the body of LOC100288798 (C1 and C2), two independently obtained KBM7 clones with gene trap cassette insertion 3kb downstream LOC100288798 transcriptional start site (TSS) (3kb1 and 3kb2), one independently obtained KBM7 clone with gene trap cassette insertion 100kb downstream LOC100288798 TSS replicated twice at the thawing step (100kb1 and 100kb2). We isolated total RNA from all th 8 cell lines, applied DNAseI treatment and ribosomal RNA depletion, and thhen prepared strand-specific RNA-seq libraries, which were pooled in equal molarities and sequenced using Illumina HiSeq 2000 (8 pooled samples were sequence on 2 lanes). We performed 50bp single-end RNA-seq. We used these 8 samples (4 untreated: WT2, WT3, C1, C2 and 4 treated:3kb1, 3kb2, 100kbk1, 100kb2) to analyze genome-wide gene deregulation associated with LOC100288798 lncRNA truncation
Publication Title
A human haploid gene trap collection to study lncRNAs with unusual RNA biology.
Sample Metadata Fields
No sample metadata fields
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