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GSE18736
Homo sapiens
33 Downloadable Samples
Affymetrix Human Genome U133A Array (hgu133a)
Description
MALT lymphoma is characterized by t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/BCL10-IGH and t(14;18)(q32;q21)/IGH-MALT1, which commonly activate the NF-B pathway. Gastric MALT lymphomas harboring such translocation do not respond to H. pylori eradication, while those without translocation can be cured by antibiotics. To understand the molecular mechanism of these different MALT lymphoma subgroups, we performed gene expression profiling analysis of 24 MALT lymphomas (15 translocation-positive, 9 translocation-negative). Gene set enrichment analysis (GSEA) of the NF-B target genes and 4394 additional gene sets covering various cellular pathways, biological processes and molecular functions showed that translocation-positive MALT lymphomas are characterized by an enhanced expression of NF-B target genes, particularly TLR6, CCR2, CD69 and BCL2, while translocation-negative cases were featured by active inflammatory and immune responses, such as IL8, CD86, CD28 and ICOS. Separate analyses of the genes differentially expressed between translocation-positive and negative cases and measurement of gene ontology term in these differentially expressed genes by hypergeometric test reinforced the above findings by GSEA. Finally, expression of TLR6, in the presence of TLR2, enhanced both API2-MALT1 and BCL10 mediated NF-B activation in vitro. Our findings provide novel insights into the molecular mechanism of MALT lymphomas with and without translocation, potentially explaining their different clinical behaviors.
Publication Title
Differential expression of NF-kappaB target genes in MALT lymphoma with and without chromosome translocation: insights into molecular mechanism.
Sample Metadata Fields
No sample metadata fields
View Samples- Caenorhabditis elegans
- 20 Downloadable Samples
Illumina HiSeq 1500
Description
Repetitive sequences derived from transposons make up a large fraction of eukaryotic genomes and must be silenced to protect genome integrity. Repetitive elements are often found in heterochromatin; however, the roles and interactions of heterochromatin proteins in repeat regulation are poorly understood. Here we show that a diverse set of C. elegans heterochromatin proteins act together with the piRNA and nuclear RNAi pathways to silence repetitive elements and prevent genotoxic stress in the germ line. Mutants in genes encoding HPL-2/HP1, LIN-13, LIN-61, LET-418/Mi-2, and H3K9me2 histone methyltransferase MET-2/SETDB1 also show functionally redundant sterility, increased germline apoptosis, DNA repair defects, and interactions with small RNA pathways. Remarkably, fertility of heterochromatin mutants could be partially restored by inhibiting cep-1/p53, endogenous meiotic double strand breaks, or the expression of MIRAGE1 DNA transposons. Functional redundancy among these factors and pathways underlies the importance of safeguarding the genome through multiple means. Overall design: Synchronized, starved L1 stage worms were grown on NGM plates under one of two conditions. Condition 1: growth was at 20°C (hpl-2, let-418, lin-61, met-2 set-25, and wild-type N2) until the L4 stage and then worms were shifted to 25°C for 15-18 hours until they reached young adult stage. Condition 2: growth was at 15°C (lin-13, prg-1, nrde-2, nrde-2; let-418, and wild-type N2) until the L4 stage, and then worms were shifted to 25°C for 15-18 hours until they reached young adult stage. Worms were then washed off plates, flash frozen in liquid nitrogen, and stored at -80°C until use. RNA was extracted from frozen worms using TriPure (Roche). RNA was purified with Zymo Research RNA Clean and Concentrator-5 (Cambridge Bioscience) following DNase I digestion. Ribosomal RNA was depleted using Ribo-Zero rRNA Removal Kit (Human/Mouse/Rat) (Illumina). Libraries were prepared using the NEBNext Ultra Directional RNA Library Prep Kit for Illumina (New England Biolabs). Two biological replicates were prepared for each strain.
Publication Title
A team of heterochromatin factors collaborates with small RNA pathways to combat repetitive elements and germline stress.
Sample Metadata Fields
Specimen part, Subject
View Samples- Homo sapiens
- 34 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
Proper regulation of nuclear factor B (NF-B) transcriptional activity is required for normal lymphocyte function, and deregulated NF-B signaling can facilitate lymphomagenesis. We demonstrate that the API2-MALT1 fusion oncoprotein created by the recurrent t(11;18)(q21;q21) in mucosa-associated lymphoid tissue (MALT) lymphoma induces proteolytic cleavage of NF-Binducing kinase (NIK) at arginine 325. NIK cleavage requires the concerted actions of both fusion partners and generates a C-terminal NIK fragment that retains kinase activity and is resistant to proteasomal degradation. The resulting deregulated NIK activity is associated with constitutive noncanonical NF-B signaling, enhanced B cell adhesion, and apoptosis resistance. Our study reveals the gain-of-function proteolytic activity of a fusion oncoprotein and highlights the importance of the noncanonical NF-B pathway in B lymphoproliferative disease.
Publication Title
Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 19 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Comparison of t(11;18)-positive MALT lymphoma to t(11;18)-negative MALT lymphoma, with a special focus on the NF-KB pathway and it's targets
Publication Title
Cleavage of NIK by the API2-MALT1 fusion oncoprotein leads to noncanonical NF-kappaB activation.
Sample Metadata Fields
Specimen part
View Samples- Caenorhabditis elegans
- 29 Downloadable Samples
- Illumina HiSeq 1500
Description
An essential step for understanding the transcriptional circuits that control development and physiology is the global identification and characterization of regulatory elements. Here we present the first map of regulatory elements across the development and ageing of an animal, identifying 42,245 elements accessible in at least one C. elegans stage. Based on nuclear transcription profiles, we define 15,918 protein-coding promoters and 17,918 putative enhancers, and find that both types of element can drive orientation-independent transcription. Additionally, hundreds of promoters produce transcripts antisense to protein coding genes, suggesting involvement in a widespread regulatory mechanism. We find that the accessibility of most elements is regulated during development and/or ageing and that patterns of accessibility change are linked to specific developmental or physiological processes. The map and characterization of regulatory elements across C. elegans life provides a platform for understanding how transcription controls development and ageing. Overall design: Capped nuclear RNA-seq of wild-type and glp-1 was performed to monitor transcription elongation across C. elegans development and ageing. Two biological replicates were done for each time point (six developmental stages and five ageing timepoints).
Publication Title
Chromatin accessibility dynamics across <i>C. elegans</i> development and ageing.
Sample Metadata Fields
Cell line, Subject
View Samples- Homo sapiens
- 9 Downloadable Samples
- Affymetrix Human Genome U133A Array (hgu133a)
Description
The response of cells to hypoxia is characterised by co-ordinated regulation of many genes. Studies of the regulation of the expression of many of these genes by oxygen has implicated a role for the heterodimeric transcription factor hypoxia inducible factor (HIF). The mechanism of oxygen sensing which controls this heterodimeric factor is via oxygen dependent prolyl and asparaginyl hydroxylation by specific 2-oxoglutarate dependent dioxygenases (PHD1, PHD2, PHD3 and FIH-1). Whilst HIF appears to have a major role in hypoxic regulation of gene expression, it is unclear to what extent other transcriptional mechanisms are also involved in the response to hypoxia. The extent to which 2-oxoglutarate dependent dioxygenases are responsible for the oxygen sensing mechanism in HIF-independent hypoxic gene regulation is also unclear. Both the prolyl and asparaginyl hydroxylases can be inhibited by dimethyloxalylglycine (DMOG). Such inhibition can produce activation of the HIF system with enhanced transcription of target genes and might have a role in the therapy of ischaemic disease. We have examined the extent to which the HIF system contributes to the regulation of gene expression by hypoxia, to what extent 2-oxoglutarate dependent dioxygenase inhibitor can mimic the hypoxic response and the nature of the global transcriptional response to hypoxia. We have utilised microarray assays of mRNA abundance to examine the gene expression changes in response to hypoxia and to DMOG. We demonstrate a large number of hypoxically regulated genes, both known and novel, and find a surprisingly high level of mimicry of the hypoxic response by use of the 2-oxoglutarate dependent dioxygenase inhibitor, dimethyloxalylglycine. We have also used microarray analysis of cells treated with small interfering RNA (siRNA) targeting HIF-1alpha and HIF-2alpha to demonstrate the differing contributions of each transcription factor to the transcriptional response to hypoxia. Candidate transcripts were confirmed using an independent microarray platform and real-time PCR. The results emphasise the critical role of the HIF system in the hypoxic response, whilst indicating the dominance of HIF-1alpha and defining genes that only respond to HIF-2alpha.
Publication Title
Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: the role of HIF-1alpha, HIF-2alpha, and other pathways.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
Systemic sclerosis (SSc) or scleroderma is a chronic multiorgan autoimmune disease of unknown etiology characterized by vascular, immunological and fibrotic abnormalities. Several lines of evidence have shown that the endocannabinoid system (ECS) may play a role in the pathophysiology of SSc. VCE-004.8, a CBD aminoquinone derivative, is a dual PPAR?/CB2 that alleviates bleomycin (BLM)-induced skin fibrosis. Herein we report that EHP-101, an oral lipidic formulation of VCE-004.8, prevents skin and lung fibrosis and collagen accumulation in BLM challenged mice. Immunohistochemistry analysis of the skin demonstrate that EHP-101 prevents macrophage infiltration, and the expression of Tenascin C (TNC), VCAM, and the a-smooth muscle actin (SMA). In addition, a reduced expression of vascular CD31, paralleling skin fibrosis, was also prevented by EHP-101. RNAseq analysis in skin biopsies showed a clear effect of EHP-101 in the inflammatory and epithelial-mesenchymal transition transcriptomic signatures. TGF-beta regulated genes such as matrix metalloproteinase-3 (Mmp3), cytochrome b-245 heavy chain (Cybb), lymphocyte antigen 6E (Ly6e), vascular cell adhesion molecule-1 (Vcam1) and the Integrin alpha-5 (Itga5) were induced in BLM mice and repressed by EHP-101 treatment. We also intersected differentially expressed genes in EHP-101-treated mice with dataset of human scleroderma intrinsic genes and found 53 overlapped genes, including the C-C motif chemokine 2 (Ccl2) and the interleukin 13 receptor subunit alpha 1 (IL-13Ra1) genes, which have been studied as biomarkers of SSc. Altogether the results indicate that this synthetic cannabinoid qualifies as a novel compound for the management and possible treatment of scleroderma and, potentially, other fibrotic diseases. Overall design: RNA-Seq profiles were generated for six- to eight-week-old female BALB/c mice in three conditions: Control, Bleomycin and Bleomycin + EHP-101 treatment (N=2).
Publication Title
EHP-101, an oral formulation of the cannabidiol aminoquinone VCE-004.8, alleviates bleomycin-induced skin and lung fibrosis.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Mus musculus
- 6 Downloadable Samples
- Illumina HiSeq 2500
Description
Several lines of evidence have shown that the endocannabinoid system (ECS) may play a role in the pathophysiology of systemic sclerosis (SSc). Thereby, structurally different dual PPAR?/CB2 agonists such as VCE-004.8 and Ajulemic acid (AjA) have been shown to alleviate skin fibrosis and inflammation in experimental models of SSc. Since both compounds are currently being tested in humans, we were interested to identify similarities and differences in a murine model of SSc. One method available to assess this is the pharmacotranscriptomic signature of the individual compounds. To analyze the pharmacotranscriptomic signature, we used RNA-Seq to analyze the skin gene expression changes from bleomycin-induced fibrosis in mice treated orally with either AjA or EHP-101, a lipidic formulation of VCE-004.8. While both compounds prevented the upregulation of a common group of genes involved in the inflammatory and fibrotic components of the disease and the pharmacotranscriptomic signatures were similar for both compounds in some pathways, we found key differences between the compounds in several functional groups, including genes related the hypoxia, interferon-a and interferon-? response. Additionally, we found 28 specific genes with translation potential by comparing our results with a list of intrinsic human scleroderma genes. Inmunohistochemical analysis revealed that both EHP-101 and AjA prevented bleomycin-induced skin fibrosis, collagen accumulation, and TNC and VCAM expression. However, only EHP-101 normalized the reduced expression of vascular CD31, CD34 and Von Willebrand factor markers, which parallels skin fibrosis, while AjA did not affect these markers. Finally, clear differences were also found in the plasmatic biomarker analysis, in which we found that EHP-101, but not AjA, enhanced the expression of some factors related to angiogenesis and vasculogenesis. Altogether the results indicate that dual PPAR?/CB2 agonists qualify as a novel therapeutic approach for the treatment of SSc and other fibrotic diseases as well, and that EHP-101 has unique mechanisms of action related to the pathophysiology of SSc which could be beneficial in treatment of this complex disease with no current therapeutic options. Overall design: RNA-Seq profiles were generated for six- to eight-week-old female BALB/c mice in four conditions: Control, Bleomycin, Bleomycin + EHP-101 treatment and Bleomycin + Ajulemic acid treatment. Please note that the "raw_counts_newsamples.txt" includes raw counts obtained from featureCounts for the samples included in this entry and the "raw_counts_merged.txt" includes raw counts obtained from merging the counts of the samples from this entry with the counts of the samples from the GSE115503 entry.
Publication Title
Cannabinoid derivatives acting as dual PPARγ/CB2 agonists as therapeutic agents for systemic sclerosis.
Sample Metadata Fields
Specimen part, Cell line, Subject
View Samples- Homo sapiens
- 12 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
The overall cellular response to oxidative stress generated by Ero1 in the lumen of the mammalian endoplasmic reticulum (ER) is poorly characterized. Here, we investigate the effects of overexpressing a hyperactive mutant (C104A/C131A) of Ero1.
Publication Title
Hyperactivity of the Ero1α oxidase elicits endoplasmic reticulum stress but no broad antioxidant response.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Clariom S Human array (clariomshuman)
Description
MiR-1246 was found to promote tumorigenesis and metastasis in sevearl cancer types. In the context of tumor microenvironment, tumor-associated macrophages are a central part typically correlated with poor prognosis.
Publication Title
Mutant p53 cancers reprogram macrophages to tumor supporting macrophages via exosomal miR-1246.
Sample Metadata Fields
Specimen part
View Samples