Nr4a2 as a transcription factor sustaining immunosuprssion in glioma
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE185758 | GEO | 2023/01/08
REPOSITORIES: GEO
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Project description:Glioma is the most common type of intracranial tumor and accounts for 75% of malignant brain tumors. Glioblastoma (GBM) is the most malignant form of glioma, with strong invasive capabilities and a high relapse rate even after treatment. Here, our RNA seqencing analysis of BV2 cells treated by H2O2 and si-Nr4a2 reveal the effect of oxdiative stress and Nr4a2-knockdown on phenotype of microglia. Chip-seqencing andlysis of BV2 cells by anti-Nr4a2 antibody is to find the target genes regulated by Nr4a2. Overall, our results reveal that Nr4a2 as the major transcription factors for microglia involved in immunosuppression of glioma.
2023-01-08 | GSE185759 | GEO
Project description:Nr4a2 as a transcription factor sustaining immunosuprssion in glioma
| PRJNA770677 | ENA
Project description:Murine BV2 microglia cells were transfected either with siRNA negative control or siRNA against caspase-3 for 48h. Later on some the of the BV2 transfected cells were co-cultured with C6 glioma cells during 6h. We used the SA Biosciences Mouse Wound Healing PCR Array (PAMM-121Z) to quantitate gene expression of relevant genes related to the wound healing process Glioma cells recruit and exploit microglia, resident immune cells of the brain, for their proliferation and invasion capability. The underlying molecular mechanism used by glioma cells to transform microglia into a tumor-supporting phenotype remains elusive. Here, we report that glioma-induced microglia conversion is coupled to a reduction of basal microglial caspase-3 activity, increased S-nitrosylation of mitochondria-associated caspase-3 through inhibition of thioredoxin-2 activity, and demonstrate that caspase-3 inhibition regulates microglial tumor-supporting function. Further, we identified nitric oxide synthase-2 (NOS2) activity originating from the glioma cells as a driving stimulus in the control of microglial caspase-3 activity. Repression of glioma NOS2 expression in vivo led to reduction in both microglia recruitment and tumor expansion, whereas depletion of the microglial caspase-3 gene promoted tumor growth. This study provides evidence that the inhibition of Trx2-mediated denitrosylation of SNO-procaspase-3 is part of the microglial pro-tumoral activation pathway initiated by glioma cancer cells. qPCR gene expression profiling. Three independent experiments of siControl BV2 monoculture, siCaspase3 BV2 monoculture, siControl BV2 cocultured 6h with C6 glioma cells and siCaspase3 BV2 cocultured 6h with C6 glioma cells. Equal amount total RNA from each culture was used for the gene expression analysis. Please note that the raw data for three independent experiments (prior to averaging the data) is provided in the 'Raw_Data_File_with_the_Ct_values_for_3_indep_experiments.txt'.
2016-07-26 | E-GEOD-84772 | biostudies-arrayexpress
Project description:Chip-seq data of BV2 cells by anti-Nr4a2 antibody
| PRJNA770678 | ENA
Project description:Murine BV2 microglia cells were transfected either with siRNA negative control or siRNA against caspase-3 for 48h. Later on some the of the BV2 transfected cells were co-cultured with C6 glioma cells during 6h. We used the SA Biosciences Mouse Wound Healing PCR Array (PAMM-121Z) to quantitate gene expression of relevant genes related to the wound healing process Glioma cells recruit and exploit microglia, resident immune cells of the brain, for their proliferation and invasion capability. The underlying molecular mechanism used by glioma cells to transform microglia into a tumor-supporting phenotype remains elusive. Here, we report that glioma-induced microglia conversion is coupled to a reduction of basal microglial caspase-3 activity, increased S-nitrosylation of mitochondria-associated caspase-3 through inhibition of thioredoxin-2 activity, and demonstrate that caspase-3 inhibition regulates microglial tumor-supporting function. Further, we identified nitric oxide synthase-2 (NOS2) activity originating from the glioma cells as a driving stimulus in the control of microglial caspase-3 activity. Repression of glioma NOS2 expression in vivo led to reduction in both microglia recruitment and tumor expansion, whereas depletion of the microglial caspase-3 gene promoted tumor growth. This study provides evidence that the inhibition of Trx2-mediated denitrosylation of SNO-procaspase-3 is part of the microglial pro-tumoral activation pathway initiated by glioma cancer cells.
2016-07-26 | GSE84772 | GEO
Project description:After exposure to drugs of abuse, the reward circuit can experience persistent changes that are thought to underlie relapse behavior. These changes can be epigenetic in nature, and here we identify an epigenetic regulator of memory processes, nuclear orphan receptor subfamily4 groupA member2 (NR4A2 aka NURR1), as necessary for relapse to cocaine-seeking behavior. Nr4a2 is an epigenetically regulated immediate early gene and transcription factor that is highly expressed in the medial habenula (MHb). Despite the well-studied contributions of the MHb to nicotine-associated behaviors, the MHb is not classically included in reward circuits. Therefore, the role of MHb NR4A2 in cocaine-seeking and relapse behavior remains largely unknown. This is a key open question as NR4A2 is a powerful regulator of memory processes dependent on epigenetic mechanisms. In this study, we examined the role of MHb NR4A2 in cued reinstatement of cocaine self-administration in mice, and found that over-expressing a dominant negative form of Nr4a2 (Nurr2c) in the MHb results in a near complete block of relapse-like behavior. We used single-nucleus transcriptomics to characterize the molecular cascade following the manipulation of Nr4a2, revealing changes in transcriptional networks related to addiction, neuroplasticity, and glutamatergic signaling. Together, these results place the MHb in the reward circuit as a pivotal regulator of relapse behavior and demonstrate the importance of NR4A2 as a key mechanism driving relapse behavior in the MHb.
2024-03-01 | GSE208081 | GEO
Project description:Sustained elevation of sympathetic activity is an important contributor to pathological cardiac hypertrophy, ventricular arrhythmias, and left ventricular contractile dysfunction in chronic heart failure. The orphan nuclear receptor NR4A2 is an immediate early response gene activated in the heart under beta-adrenergic stimulation. The goal of this study was to identify the transcriptional remodeling events induced by NR4A2 expression in cardiomyocytes, and their impact on the physiological response of those cells to sustained beta-adrenergic stimulation. Treatment of adult rat ventricular myocytes (ARVMs) with isoproterenol induced a rapid (< 4 hours) but transient (< 24 hours) increase in NR4A2 expression levels that was accompanied by increased nuclear localization of the transcription factor. Adenovirus-mediated overexpression of NR4A2 modulated the expression of genes linked to adrenoceptor signaling, calcium signaling, cell growth and proliferation, and counteracted the increase in protein synthesis rate and cell surface area mediated by chronic isoproterenol stimulation. In consistence with those findings, NR4A2 overexpression also blocked the phosphorylative activation of ERK1/2, Akt, and of their downstream effector in protein synthesis p70S6K. Prominent among the transcriptional changes induced by NR4A2 was the > 7-fold up-regulation of the dual-specificity phosphatases DUSP2 and DUSP14, two known inhibitors of ERK1/2. Pre-treatment of NR4A2-overexpressing cardiomyocytes with the DUSPs inhibitor BCI prevented the inhibition of ERK1/2 and p70S6K following isoproterenol stimulation. In conclusion, our results suggest that NR4A2 acts as a novel negative feedback regulator of the beta-adrenergic receptor-mediated growth response in cardiomyocytes, and this at least partly through DUSP-mediated inhibition of ERK1/2 signaling.
2018-11-27 | GSE122911 | GEO
Project description:We have developed an assay to test the neuroprotective properties of compounds using stem cellM-bM-^@M-^Sderived motor neurons and astrocytes, together with activated microglia as a stress paradigm. Hit compounds were discovered and the transcriptional response on activated BV2 cells was tested. The BV2 cell line was activated with LPS and IFN-M-NM-3 and treated with hit compound for 4 hr.
2012-11-03 | E-GEOD-37612 | biostudies-arrayexpress
Project description:Understanding microglial states in the aging brain has become crucial, especially with the discovery of numerous Alzheimer’s disease (AD) risk and protective variants in genes such as INPP5D and TREM2, which are essential to microglia function in AD. Here we present a thorough examination of microglia-like cells and primary mouse microglia at the proteome and transcriptome levels to illuminate the roles these genes and the proteins they encode play in various cell states. First, we compared the proteome profiles of wildtype and INPP5D (SHIP1) knockout primary microglia. Our findings revealed significant proteome alterations only in the homozygous SHIP1 knockout, revealing its impact on the microglial proteome. Additionally, we compared the proteome and transcriptome profiles of commonly used in vitro microglia BV2 and HMC3 cells with primary mouse microglia. Our results demonstrated a substantial similarity between the proteome of BV2 and mouse primary cells, while notable differences were observed between BV2 and human HMC3. Lastly, we conducted targeted lipidomic analysis to quantify different phosphatidylinositols (PIs) species, which are direct SHIP1 targets, in the HMC3 and BV2 cells. This in-depth omics analysis of both mouse and human microglia enhances our systematic understanding of these microglia models.
2024-05-10 | PXD052147 | JPOST Repository
Project description:Glioma initiating cells (GICs) are considered responsible for the therapeutic resistance and recurrence of malignant glioma. To clarify the molecular mechanism of GIC maintenance/differentiation, we established GIC clones from GBM patient tumors having the potential to differentiate into malignant gliomas in mouse intracranial xenograft, and established an in vitro glioma induction system by using serum stimulation. Upon the serum stimulation, the GIC spheres showed increased cellular proliferation, motility, filopodia/lameripodia formation and adhesion to the culture dishes. Simultaneously, the NSC marker proteins such as CD133 and Sox2 were down-regulated, and the astrocyte/glioma marker GFAP and the malignancy marker CD44 dramatically up-regulated. To identify genes/proteins whose expression changes dynamically during the differentiation of GICs into glioma cells, these GICs were subjected to DNA microarray/iTRAQ based integrated proteomics.
2013-01-26 | GSE43762 | GEO