Lipopolysaccharide-dependent transcriptional regulation of PU.1 in microglial cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE134701 | GEO | 2020/07/23
REPOSITORIES: GEO
Shared Molecules
Only show the datasets with similarity scores above: 0.5
Threshold
0.5
Similar Datasets
Project description:Lipopolysaccharide-dependent transcriptional regulation of PU.1 in microglial cells
| PRJNA556190 | ENA
Project description:More than forty loci contribute to genetic risk for Alzheimer’s disease (AD). These risk alleles are enriched in myeloid cell enhancers suggesting that microglia, the brain-resident macrophages, contribute to AD risk. We have previously identified SPI1/PU.1, a master regulator of myeloid cell development in the brain and periphery, as a genetic risk factor for AD. Higher expression of SPI1 is associated with increased risk for AD, while lower expression is protective. To investigate the molecular and cellular phenotypes associated with higher and lower expression of PU.1 in microglia, we used stable overexpression and knock-down of PU.1 in BV2, an immortalized mouse microglial cell line. Transcriptome analysis suggests that reduced PU.1 expression suppresses expression of homeostatic genes similar to the disease-associated microglia response to amyloid plaques in mouse models of AD. Moreover, PU.1 knock-down resulted in activation of protein translation, antioxidant action and cholesterol/lipid metabolism pathways with a concomitant decrease of pro-inflammatory gene expression. PU.1 overexpression upregulated and knock-down downregulated phagocytic uptake in BV2 cells independent of the nature of the engulfed material. However, cells with reduced PU.1 expression retained their ability to internalize myelin similar to control albeit with a delay, which aligns with their anti-inflammatory profile. Here we identified several microglial responses that are modulated by PU.1 expression levels and propose that risk association of PU.1 to AD is driven by increased pro-inflammatory response due to increased viability of cells under cytotoxic conditions. In contrast, low expression of PU.1 leads to increased cell death under cytotoxic conditions accompanied by reduced pro-inflammatory signaling that decreased A1 reactive astrocytes signature supporting the protective effect of SPI1 genotype in AD. These findings inform future in vivo validation studies and design of small molecule screens for therapeutic discovery in AD.
2020-12-07 | GSE162526 | GEO
Project description:We hypothesized that aged garlic extract, and a pure compound from it, FruArg, can repress the genetic response induced by lipopolysaccharide (LPS). We applied gene expression profiling to understand the potential mechanisms of the protective effects of AGE and FruArg against LPS stress in BV-2 cells. Gene expression profiling showed that AGE repressed the transcriptome alteration induced by LPS. FruArg, as an active compound in AGE, accounted for AGE's protective effects. These results suggest that AGE and FruArg are capable of alleviating oxidative and neuroinflammatory responses stimulated by LPS in BV-2 cells.
2016-10-01 | GSE87531 | GEO
Project description:In X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, microglial defect is suggested to prime and amplify the neuroinflammatory process. By using CRISPR/Cas9 gene editing, we recently established BV-2 microglial cell models to study the impact of dysfunctional peroxisomal b-oxidation and demonstrated the emergence of a disease-associated microglial signature in these cell lines. Their transcriptomic analysis suggested consequences on immune response. To go further, we have used RNA-sequencing and functional assays related to immune response to compare the WT and mutant BV-2 cell lines in basal conditions or upon lipopolysaccharide (LPS) stimulation.
2024-01-01 | GSE237635 | GEO
Project description:Transcriptional profiling of BV-2 microglial cells comparing control untreated BV-2 cells with LPS-treated BV-2 cells or obovatol/LPS-treated BV-2 cells. Objective was to determine the effect of obovatol on LPS-induced gene expression in microglia.
2010-07-05 | GSE17069 | GEO
Project description:We used mRNA-seq analysis to explore the transcriptional response induced in BV-2 cells by stable overexpression Siglec-F and related human Siglec receptors compared to loss-of-function 2xY->F mutant receptors.
2020-09-01 | GSE149153 | GEO
Project description:Primary effusion lymphoma (PEL), which is an aggressive lymphoma associated with Kaposi sarcoma-associated herpesvirus/human herpes virus-8 (KSHV/HHV-8), is refractory to standard chemotherapy, and exhibits a poor prognosis. Although PU.1 is down-regulated in PEL among B-cell transcription factors, the potential role of its reduction remains to be elucidated. In this investigation, we analyzed the DNA methylation of PU.1 cis-regulatory elements in PEL and the effect of restoring PU.1 on PEL cells. The expression of PU.1 mRNA was down-regulated in PEL cells. The promoter and enhancer regions of the PU.1 gene were highly methylated. The restoration of PU.1 inhibited cell growth and induced apoptosis in PEL cells. A microarray analysis revealed that interferon-stimulated genes (ISGs) including pro-apoptotic ISGs were strongly increased in BCBL-1 cells after the induction of PU.1. The up-regulation of PU.1 induced the transactivation of pro-apoptotic ISG promoters, such as the XAF1, OAS1, and TRAIL promoters, in reporter assays. Mutations at the PU.1 binding sites suppressed its transactivation. We confirmed the binding of PU.1 to the XAF1, OAS1, and TRAIL promoters in a chromatin immunoprecipitation assay. PU.1 suppressed ORF57 activation by inducing IRF7. The reinduction of PU.1 reduced formation of ascites and lymphoma cell infiltration of distant organs in PEL xenograft model mice. These results suggest that PU.1 plays a role in tumor suppression in PEL and its down-regulation is associated with PEL development. Up-regulation of PU.1 with demethylation agents may be a novel therapeutic strategy for PEL.
2019-02-28 | GSE97318 | GEO
Project description:The aging process is marked by a time-dependent deterioration in cellular functions, particularly the immune and neural systems. Understanding the phenotype acquisition of microglia, the sentinel immune cells of the brain, is crucial for understanding the nature of age-related neurological diseases. However, the specific phenotype adopted by microglia during aging remains a subject of debate and is contingent on the chosen experimental model. To address these unresolved questions, we employed a novel and highly controlled approach utilizing long-term cultivated BV-2 microglia, exempted of additional external stimuli. Our findings revealed that aged microglial cells, in comparison to their younger counterparts, acquire a distinct gene expression profile, primarily characterized by alterations in microglial immune response. Indeed, pro-inflammatory stimulated aged and young BV-2 microglia exhibited similar transcriptomic profiles, yet the response intensity to stimulus was markedly muted in the aged microglia. Functional neurotoxic assays confirmed diminished neuronal death in coculture with aged, activated microglia, underscoring a compromised immune response. Furthermore, a subsequent comparative analysis of aged BV-2 microglia with established transcriptomic microglial datasets from aged mice and humans identified 13 overlapping genes, laying the foundation for identifying core microglial aging signature. Particularly noteworthy were SLC16A3 and P2RY13, which consistently exhibited upregulation and downregulation, respectively, across all datasets. Additionally, four other genes—CAPG, LGALS3BP, NRIP1, and P2RY12—were found to share regulatory patterns in response to both aging and extrinsic activation. In-depth investigation focused on SLC16A3, encoding the high-affinity lactate transporter MCT4, revealed disruptions in extracellular acidification rate and lactate concentration with age. Microglial purine sensing and motility capacities, regulated by P2RY12/P2RY13, displayed age-related alterations. Remarkably, protein analysis in human brain tissue validated the observed upregulation of MCT4 and downregulation of P2RY12 in aged microglia. In conclusion, our study unveils a distinct phenotype in aged microglia characterized by compromised immune responsiveness. Through the integration of in vitro cultured BV-2 microglia with primary microglia datasets, we identify critical molecular determinants of microglial cellular aging confirmed in human aged brain tissue. This comprehensive approach offers potential insights for understanding and potentially reprogramming aged microglia, with implications for combating age-related neurological disorders.
2025-01-17 | GSE287220 | GEO
Project description:Neutrophils are essential first line defense cells against invading pathogens, yet their inappropriate activation contributes to immunological diseases and can cause collateral tissue damage. However, if and how neutrophils cell-intrinsically titrate their inflammatory response remains unknown. Here, we conditionally deleted PU.1, a key myeloid transcription factor, from the neutrophils of mice undergoing fungal infection, and then performed comprehensive epigenomic profiling. We find that a major function of PU.1 is to restrain the neutrophils’ immune response by broadly suppressing genomic enhancer outputs via recruiting histone deacetylase activity, thereby limiting the immune-stimulatory AP1-transcription factor JUNB from entering chromatin. Thus, neutrophils rely on a direct PU.1 repressor function as rheostat of the inflammatory chromatin state, safeguarding their epigenome from undergoing uncontrolled activation prior to pathogenic stimulation. We performed whole transcriptome profiling of neutrophils (Gr1+) flow-sorted from the BM of PU.1 WT and PU.1 KO mice, and found nearly 1000 differentially expressed transcripts, 443 of which were decreased and 555 increased in PU.1-deleted neutrophils. Functional annotations of the differentially expressed transcripts revealed that differentiation-associated gene sets were not significantly changed in the neutrophils from PU.1∆Neu mice. In contrast, the top ranked gene ontology (GO) sets downregulated in PU.1∆Neu neutrophils represented immunological terms such as inflammatory response, NFκB activity and Toll-like receptor (TLR) signalling.
2019-03-19 | GSE110859 | GEO