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GSE6903
Mus musculus
6 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
effect of over-expression LIGHT on T cells for the liver gene expression
Publication Title
Lymphotoxin beta receptor-dependent control of lipid homeostasis.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 30 Downloadable Samples
- Illumina HumanHT-12 V3.0 expression beadchip
Description
Design: Persistent latently infected CD4+ T cells represent a major obstacle to HIV eradication. Histone deacetylase inhibitors (HDACis) are a promising activation therapy in a shock and kill strategy. However, off-target effects of HDACis on host gene expression are poorly understood in primary cells of the immune system. We hypothesized that HDACi-modulated genes would be best identified with a dose response analysis. Methods: Resting primary CD4+ T cells were treated with increasing concentrations (0.34, 1, 3, or 10 M) of the HDACi, suberoylanilide hydroxamic acid (SAHA), for 24 hours and then subjected to microarray gene expression analysis. Genes with dose-correlated expression were identified with a likelihood ratio test using Isogene GX and a subset of these genes with a consistent trend of up or downregulation at each dose of SAHA were identified as dose-responsive. Histone modifications were characterized in promoter regions of the top 6 SAHA dose-responsive genes by RT-qPCR analysis of immunopreciptated chromatin (ChIP). Results: A large number of genes were shown to be up (N=657) or down (N=725) regulated by SAHA in a dose-responsive manner (FDR p-value < 0.05 and fold change |2|). Several of these genes (CTNNAL1, DPEP2, H1F0, IRGM, PHF15, and SELL) are potential in vivo biomarkers of SAHA activity. SAHA dose-responsive gene categories included transcription factors, HIV restriction factors, histone methyltransferases, and host proteins that interact with HIV proteins or the HIV LTR. Pathway analysis suggested net downregulation of T cell activation with increasing SAHA dose. Histone acetylation was not correlated with host expression, but plausible alternative mechanisms for SAHA-modulated expression were identified. Conclusions: Numerous host genes in CD4+ T cells are modulated by SAHA in a dose-responsive manner, including genes that may negatively influence HIV activation from latency. Our study suggests that SAHA influences gene expression through a confluence of several mechanisms, including histone acetylation, histone methylation, and altered expression and activity of transcription factors.
Publication Title
Dose-responsive gene expression in suberoylanilide hydroxamic acid-treated resting CD4+ T cells.
Sample Metadata Fields
Specimen part, Subject
View Samples- Mus musculus
- 3 Downloadable Samples
Illumina HiSeq 2000
Description
To study the role of epigenetics and hormones on hematopoietic stem cell function, hematopoietic stem and progenitor (LSK) cells were sorted from E14.5 embryos of wild-type, DNMT3B7 hemizygous or DNMT3B7 homozygous genotype. The expression analysis was performed to provide information regarding the mechanism by which hormones regulate hematopoiesis. Overall design: Hematopoietic stem and progenitor (LSK) cells from E14.5 murine embryonic fetal livers of wild-type, or DNMT3B7 transgenic genotypes were flow-sorted, and RNA isolated for expression analysis by RNA-Sequencing
Publication Title
Epigenetic Control of Apolipoprotein E Expression Mediates Gender-Specific Hematopoietic Regulation.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 34 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302), Affymetrix Mouse Genome 430A 2.0 Array (mouse430a2)
Description
We previously observed that formation of aorta and innominate artery atherosclerotic lesions in the intima of hyperlipidemic apoE-deficient mice but not wild-type mice was accompanied by a marked age-dependent adventitial T cell infiltration. As the mice aged, adventitial T cells formed T/T cell-, T/B cell-, and T/B/dendritic cell aggregates adjacent to atherosclerotic lesions. Some of the adventitial infiltrates formed large clusters of various immune cells including T cells, B cells (centrocytes, follicular mantle cells), dendritic cells, follicular dendritic cells, and plasma cells with preferential formation in the suprarenal portion of the abdominal aorta. These data demonstrated that the immune lineage cell composition of atherosclerotic lesions and adventitia were distinct: The macrophage-foam cell-, T cell-, and SMC-dominated cell composition of atherosclerosis lesions versus the presence of immune cells capable of carrying out antigen-dependent T cell-driven humoral immune responses in the adventitia also indicated that immune reactions carried out in lesions or the adventitia are fundamentaly different. To distinguish between immunity-regulating genes in atherosclerosis lesions versus the adventitia, a combination of microarray profiling and laser capture microdissection was used. Stringent filters revealed 1163 differentially up-regulated probesets in apoE-/- mouse aortae at 78 weeks (w) versus 6 w. A fuzzy c-means cluster algorythm identified 2 clusters that significantly differed in their slope angles between time points: An apparent atherosclerosis cluster consisted of 771 probesets and an apparent adventitia cluster consisted of 392 probesets. Up-regulated genes at 32 w mirrored the influx of monocyte/macrophages into intima lesions whereas genes up-regulated between 32-78 w mirrored adventitial inflammation. To segregate both clusters into separate gene ontology (GO) molecular function groups, we determined statistically significant up-regulation (unpaired Student t-test; p < 0.05) between 6-32 w for the atherosclerosis cluster and between 32-78 w for the adventitia cluster. Among others, GO molecular function terms cytokine activity, cytokine binding, and immunoglobulin binding in the atherosclerosis cluster and cytokine activity, chemokine receptor activity, and antigen binding in the ATLO cluster suggested candidate genes in relation to inflammation triggered by macrophages or adventitia infiltration, respectively. Among other prototype atherosclerosis genes such as Itgax (complement receptor 4), Cd68, Lysz (lysozyme), Vcam1, and Icam1, the atherosclerosis cluster showed markedly overrepresented prototype macrophage/foam cell genes regulating inflammation in cytokine activity (GO: 0005125): Spp1 (osteopontin) and Il6; in cytokine binding (GO: 0019955) Cd74, Il10rb, Ccr2, and Ccr5; and in immunoglobulin binding (GO: 00119865) the proinflammatory galactose-binding lectin Lgals3, as well as genes in scavenger receptor activity and lipid transporter activity. By contrast, the adventitia cluster showed overrepresented genes regulating B cell recruitment, B cell maturation, germinal center formation, and autoimmunity in cytokine activity including Cxcl13, Ccl21, and Ltb, in CXC chemokine receptor activity the secondary lymphoid organ counterreceptor of CXCL13 Blr1 (also known as Cxcr5), Cxcr3, and Cxcr6; and in antigen binding several histocompatibility-2 loci and various markedly expressed immunoglobulin genes. As embryonic lymph node development and tertiary lymphoid organ neogenesis share common features signal intensities of genes specifying the GO molecular function term lymph node development (GO: 0048535) were examined in arrays prepared from wild-type and apoE-/- aortae. These results showed that Id2, Nfkb1, and Ltbr were constitutively expressed at significant levels in aortae of both mouse genotypes whereas other genes including Lta, Ltb, Glycam1, and the two lymphorganogenic genes Cxcl13 and Ccl21 were induced at 78 w in apoE-deficient aortae only. Thus, genes expressed by macrophage-foam cells and genes regulating ATLO neogenesis, embryonic lymph node development, or B cell maturation were constitutively expressed in the arterial wall in both genotypes or emerged in a stepwise fashion at 32 w and 78 w. To verify microarray signal intensity data, separate aortae extracts were examined by quantitative RT-PCR (QRT-PCR) analyses of wild-type and apoE-deficient mice at 32 and 78 w. These data showed that array signal values accurately reflected gene transcripts. Cell lineage analyses of the adventitial infiltrate and kinetic aorta microarray- and QRT-PCR analyses thus provided circumstantial evidence that immune responses in atherosclerosis intima lesions and the adventitia were distinct. To examine this possibility further, we selected areas of the abdominal aorta burdened with advanced lesions and separated lesions and corresponding adventitial infiltrates of 78 w old apoE-deficient mice by laser dissection microscopy. In addition, adventitiae of aorta segments that were not associated with adjacent lesions and adventitiae of wild-type mice were prepared. Consistent with the lack of a major adventitial leukocyte infiltration, wild-type adventitiae showed gene expression levels that were similar to lesion-free adventitiae of apoE-deficient mice indicating that atherosclerotic lesions directly affected adventitial inflammation in a segmental fashion. Stringent filter criteria identified genes that were differentially expressed in adventitiae and atherosclerotic lesions. Statistical analyses of overrepresented genes in GO molecular function or biological process groups were particularly instructive in cytokine activity, cytokine binding, antigen processing and presentation as well as in lymph node development. Thus, adventitiae in aorta segments with associated atherosclerotic lesions in cytokine activity showed overrepresentation of genes known to be associated with tertiary lymphoid organ formation including Cxcl13, Ccl21, and Ltb, whereas atherosclerotic lesions showed overrepresentation of prototype atherosclerosis-associated genes Ssp1 (osteopontin), Bmp4 (bone morphogenic protein 4), and Cxc3cl1 (fractalkine); in cytokine binding adventitiae showed overrepresentation of receptors implicated in B cell immunity and autoimmunity including Brl1 (counterreceptor for CXCL13), Ccr7, Tnfrsf4, and Cxcr3 whereas lesions showed overrepresentation of inflammatory mediator receptors including Tnfrs1b, Tgfbr1, and Il7r; moreover, in antigen processing and presentation, adventitiae showed overrepresentation of several histocompatibility loci; additional adventitial gene expression overrepresentations were observed in lymph node development (Fas, SpiB, Ltb, Flt3) whereas lesions showed expression of prototype macrophage genes including Tlr4, Tgfb1, and Tgfb2. These data provide comprehensive topographical transcriptome information in adventitial tissue adjacent to atherosclerotic lesions versus lesions and are expected to form the basis for future cell lineage expression analyses using single cell detection methodology including ISH.
Publication Title
Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 24 Downloadable Samples
- Illumina HiSeq 3000
Description
Glioblastoma is the most common primary malignant brain tumor in adults and associated with poor survival. Standard-of-care chemotherapy and radiation confer a median overall survival of under two years. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab, a programmed cell death protein 1 (PD-1) monoclonal antibody, in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical PD-1 blockade alone (hazard ratio = 0.39; P = 0.04, log-rank test). Neoadjuvant PD-1 blockade was associated with upregulation of T cell and interferon-?-related genes, but downregulation of cell cycle related genes within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 (PD-L1) in the tumor microenvironment was observed more frequently in the neoadjuvant group than in tumors obtained from patients treated only in the adjuvant setting. Similarly, neoadjuvant pembrolizumab was associated with clonal T cell expansion and the overlap of T cell receptors between tumor and blood, decreased PD-1 expression in T cells and a decreasing peripheral monocytic population. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances the local and systemic anti-tumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor. This trial was registered with ClinicalTrials.gov under the identifier NCT02852655 (https://clinicaltrials.gov/ct2/show/NCT02852655). Overall design: This dataset contains the transcriptomes of recurrent glioblastoma with either neoadjuvant (1 dose) or adjuvant pembrolizumab treatment
Publication Title
Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma.
Sample Metadata Fields
Subject
View Samples- Homo sapiens
- 39 Downloadable Samples
- Illumina HiSeq 2000
Description
Transcriptome profiles for innate and adaptive immune stimuli important for host response against mycobacteria. Human monocyte-derived macrophages were stimulated with TLR2/1 ligand and interferon-g, stimuli present during innate and adaptive immune responses, respectively. Overall design: Human monocyte-dervided macrophages from five healthy donors were stimulated with TLR2/1L, IFN-g, or media control for 2, 6, and 24 hours. RNA-sequencing was performed on a total of 45 samples.
Publication Title
S100A12 Is Part of the Antimicrobial Network against Mycobacterium leprae in Human Macrophages.
Sample Metadata Fields
Specimen part, Subject
View Samples- Escherichia coli
- 4 Downloadable Samples
- Affymetrix E. coli Genome 2.0 Array (ecoli2)
Description
Escherichia coli 8624 and the isogenic mutants in qseE, qseF and qseG are compared to determine the role that each of the genes play in regulation of the transcriptome. These results are verified by qRT-PCR and reveal the important role of this three-component signaling system.
Publication Title
The two-component system QseEF and the membrane protein QseG link adrenergic and stress sensing to bacterial pathogenesis.
Sample Metadata Fields
No sample metadata fields
View Samples- Homo sapiens
- 8 Downloadable Samples
- Affymetrix Human Transcriptome Array 2.0 (hta20)
Description
Chronic low dose inorganic arsenic (iAs) exposure leads to changes in gene expression and epithelial-to-mesenchymal transformation. During this transformation, cells adopt a fibroblast-like phenotype accompanied by profound gene expression changes. While many mechanisms have been implicated in this transformation, studies that focus on the role of epigenetic alterations in this process are just emerging. DNA methylation controls gene expression in physiologic and pathologic states. Several studies show alterations in DNA methylation patterns in iAs-mediated pathogenesis, but these studies focused on single genes. We present a comprehensive genome-wide DNA methylation analysis using methyl-sequencing to measure changes between normal and iAs-transformed cells. Additionally, these differential methylation changes correlated positively with changes in gene expression and alternative splicing. Interestingly, most of these differentially methylated genes function in cell adhesion and communication pathways. To gain insight into how genomic DNA methylation patterns are regulated iAs-mediated carcinogenesis, we show that iAs probably targets CTCF binding at the promoter of DNA methyltransferases, regulating their expression. These findings reveal how transcription factor binding regulates DNA methyltransferase to reprogram the methylome in response to an environmental toxin.
Publication Title
Genome-wide DNA methylation reprogramming in response to inorganic arsenic links inhibition of CTCF binding, DNMT expression and cellular transformation.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 84 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
There are currently no biological tests that differentiate patients with bipolar disorder (BPD) from healthy controls. While there is evidence that peripheral gene expression differences between patients and controls can be utilized as biomarkers for psychiatric illness, it is unclear whether current use or residual effects of antipsychotic and mood stabilizer medication drives much of the differential transcription. We therefore tested whether expression changes in first-episode, never-medicated bipolar patients, can contribute to a biological classifier that is less influenced by medication and could potentially form a practicable biomarker assay for BPD.
Publication Title
Utilization of never-medicated bipolar disorder patients towards development and validation of a peripheral biomarker profile.
Sample Metadata Fields
Sex, Age, Specimen part
View Samples- Homo sapiens
- 8 Downloadable Samples
- Illumina HiSeq 2000
Description
Huge efforts are made to engineer safe and efficient genome editing tools. An alternative might be the harnessing of ADAR-mediated RNA editing. We now present the engineering of chemically optimized antisense oligonucleotides that recruit endogenous human ADARs to edit endogenous transcripts in a simple and programmable way, an approach we refer to as RESTORE. Notably, RESTORE was markedly precise, and there was no evidence for perturbation of the natural editing homeostasis. We applied RESTORE to a panel of standard human cell lines, but also to several human primary cells including hepatocytes. In contrast to other RNA and DNA editing strategies, this approach requires only the administration of an oligonucleotide, circumvents the ectopic expression of proteins, and thus represents an attractive platform for drug development. In this respect we have shown the repair of the PiZZ mutation causing a1-antitrypsin deficiency and the editing of phosphotyrosine 701 in STAT1. Overall design: Identification of off-target editing events and Interferon-a influence in HeLa cell line transfected with an ASO for RNA editing by RNA-Seq, 2 samples (ASO +/- IFN) , 2 control sample (+/-IFN), 2 biologically independent experiments for each sample, 8 samples in total
Publication Title
Precise RNA editing by recruiting endogenous ADARs with antisense oligonucleotides.
Sample Metadata Fields
Cell line, Treatment, Subject
View Samples