LXRα genomic binding in murine macrophages
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE275506 | GEO | 2024/08/27
REPOSITORIES: GEO
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Project description:The Liver X receptors (LXRα and LXRβ) are members of the nuclear receptor superfamily of transcription factors, and play key roles in the coordination of both metabolic and immune responses in macrophages. Both LXRs are expressed in macrophages and they share a high degree of sequence homology but their individual roles in different models of macrophage cultures, particularly in response to inflammation, have not been characterized. Previous studies have shown that ligand pre-treated LXRs repress the induction of pro-inflammatory cytokines in macrophages. Here, we show evidence that the expression of LXRα (but not LXRβ) is transcriptionally regulated at late phases of an LPS-induced inflammatory response in bone marrow-derived macrophages (BMDMs). Regulation of LXRα expression is controlled at the transcriptional levels by inflammatory signaling networks. Transcriptional profiling studies and ChIP-seq data identified a number of innate immune pathways whose expression is substantially controlled by LXRα in BMDMs. In summary, our data shows that LXRα plays a previously unrecognized role in innate immunity by transcriptional regulation of a battery of inflammatory genes through TLR and Type-I IFN-dependent signaling in macrophages.
2020-05-01 | GSE130586 | GEO
Project description:The Liver X receptors (LXRα and LXRβ) are members of the nuclear receptor superfamily of transcription factors, and play key roles in the coordination of both metabolic and immune responses in macrophages. Both LXRs are expressed in macrophages and they share a high degree of sequence homology but their individual roles in different models of macrophage cultures, particularly in response to inflammation, have not been characterized. Previous studies have shown that ligand pre-treated LXRs repress the induction of pro-inflammatory cytokines in macrophages. Here, we show evidence that the expression of LXRα (but not LXRβ) is transcriptionally regulated at late phases of an LPS-induced inflammatory response in bone marrow-derived macrophages (BMDMs). Regulation of LXRα expression is controlled at the transcriptional levels by inflammatory signaling networks. Transcriptional profiling studies and ChIP-seq data identified a number of innate immune pathways whose expression is substantially controlled by LXRα in BMDMs. In summary, our data shows that LXRα plays a previously unrecognized role in innate immunity by transcriptional regulation of a battery of inflammatory genes through TLR and Type-I IFN-dependent signaling in macrophages.
2022-12-31 | GSE200922 | GEO
Project description:The Liver X receptors (LXRα and LXRβ) are members of the nuclear receptor superfamily of transcription factors, and play key roles in the coordination of both metabolic and immune responses in macrophages. Both LXRs are expressed in macrophages and they share a high degree of sequence homology but their individual roles in different models of macrophage cultures, particularly in response to inflammation, have not been characterized. Previous studies have shown that ligand pre-treated LXRs repress the induction of pro-inflammatory cytokines in macrophages. Here, we show evidence that the expression of LXRα (but not LXRβ) is transcriptionally regulated at late phases of an LPS-induced inflammatory response in bone marrow-derived macrophages (BMDMs). Regulation of LXRα expression is controlled at the transcriptional levels by inflammatory signaling networks. Transcriptional profiling studies and ChIP-seq data identified a number of innate immune pathways whose expression is substantially controlled by LXRα in BMDMs. In summary, our data shows that LXRα plays a previously unrecognized role in innate immunity by transcriptional regulation of a battery of inflammatory genes through TLR and Type-I IFN-dependent signaling in macrophages.
2024-04-02 | GSE254257 | GEO
Project description:OBJECTIVE: The liver X receptor α (LXRα) is a ligand-dependent nuclear receptor and the major regulator of reverse cholesterol transport in macrophages. This makes it an interesting target for mechanistic study and treatment of atherosclerosis. METHODS AND RESULTS: We optimized a promising stilbenoid structure (STX4) in order to reach nanomolar effective concentrations in LXRα reporter-gene assays. STX4 displayed the unique property to activate LXRα effectively but not its subtype LXRβ. The potential of STX4 to increase transcriptional activity as an LXRα ligand was tested with gene expression analyses in THP1-derived human macrophages and oxLDL-loaded human foam cells. Only in foam cells but not in macrophage cells STX4 treatment showed athero-protective effects with similar potency as the synthetic LXR ligand T0901317 (T09). Surprisingly, combinatorial treatment with STX4 and T09 resulted in an additive effect on reporter-gene activation and target gene expression. In physiological tests the cellular content of total and esterified cholesterol was significantly reduced by STX4 without the undesirable increase in triglyceride levels as observed for T09. CONCLUSIONS: STX4 is a new LXRα-ligand to study transcriptional regulation of anti-atherogenic processes in cell or ex vivo models, and provides a promising lead structure for pharmaceutical development.
2013-09-05 | GSE39079 | GEO
Project description:The nuclear receptors LXRa and LXRb play a crucial role in regulating hepatic lipid metabolism. Many genes induced in response to pharmacologic LXR agonism in mouse liver have been defined; however, the transcriptional consequences of loss of LXR binding to its genomic targets are not well characterized. Here we addressed how deletion of both LXRa and LXRb from mouse liver (LXRDKO) affects the transcriptional regulatory landscape by integrating changes in LXR/RXR binding, chromatin accessibility, and gene expression. Many genes involved in fatty acid metabolism have reduced expression and chromatin accessibility at their intergenic and intronic regions in LXRDKO livers. Genes that were upregulated in LXRDKO livers have increased chromatin accessibility in their promoter regions and are enriched for those with functions not linked to lipid metabolism. We further showed that loss of LXR binding in liver reduces the activity of a broad set of hepatic transcription factors, inferred through motif accessibility. In contrast, accessibility at promoter NFY motifs is strongly increased in the absence of LXR. Surprisingly, we define small set of direct target genes for ligand-dependent LXR repression. These genes with LXR binding sites show increased expression in LXRDKO liver and reduced expression in response to LXR agonist treatment. In summary, while our results support the established roles for LXRs as ligand-dependent activators of genes linked to lipid metabolism, the binding of LXR/RXR heterodimers to the hepatic genome has broad effects on the transcriptional landscape that extend beyond its canonical function as an activator of lipid metabolic genes.
2022-01-25 | GSE191030 | GEO
Project description:LXRs (LXRa and LXRb) are widely expresded in a variety of cell types. We addressed how transient LXR activation using GW3965 impacts the cellular composition and/or transcriptional changes in the SI of WT mice.
2024-07-19 | GSE227726 | GEO
Project description:The LXR proteins, LXRα and LXRβ, are transcription factors that belong to the nuclear receptor superfamily. LXRs are activated by oxysterols and control the transcription of genes involved in the regulation of cholesterol and fatty acid metabolism. They also mediate several aspects of macrophage biology, including inflammatory responses, cell survival in response to infection and phagocytosis of apoptotic cells. LXRs share a high degree of sequence homology and most of their functions are believed to be performed similarly by LXRα and LXRβ. However, the individual, transcriptional roles of each LXR isoform have not been characterized in detail, in part due to the lack of specific experimental tools that can discriminate between LXRα and LXRβ actions. To identify common and differential transcriptional functions of LXR nuclear receptors in macrophages, we developed a cellular model of stable expression of FLAG-tagged LXRα or LXRβ in LXR-null immortalized murine bone marrow-derived macrophages (parental line published Elife. 2015 Jul 14;4:e08009. doi: 10.7554/eLife.08009). To take a deeper insight into the epigenomic features of LXR nuclear receptors, we performed chromatin immunoprecipitation coupled to next-generation sequencing (ChIP-seq) to identify genome-wide binding locations of LXRα and LXRβ in the presence of a synthetic agonist (GW3965, 1uM). Additionally, we identified genome-wide DNA locations of acetylation mark on lysine 27 of histone H3 (H3K27ac), upon LXR agonist (GW3965, 1uM) and antagonist (GW2033, 1uM) treatment. Collectively, these studies will increase our understanding of common and differential genomic actions of LXRα and LXRβ in cultured murine macrophages.
2017-10-19 | GSE104027 | GEO
Project description:Systems biology analysis of temporally-resolved phagosome proteomes following uptake via key phagocytic receptors Macrophages operate at the forefront of innate immunity, and their discrimination of pathogenic versus “self” particles is critical for a number of responses including efficient pathogen killing, antigen presentation and cytokine induction. In order to efficiently phagocytose and destroy the particles, macrophages express an array of receptors to sense and internalise prey particles. In this manuscript, particles conjugated to seven ligands representing pathogen-associated molecular patterns, immune opsonins or apoptotic cell markers were inoculated to murine bone marrow-derived macrophages (BMDMs) and proteomes of isolated phagosomes were accurately quantified among conditions and across a timecourse. While we identified a clear functional differentiation over the three timepoints, only subtle differences were detected between certain ligand-phagosomes, suggesting that triggering of receptors through a single ligand has only mild effects on phagosome proteome and function. This data shows for the first time a systematic time-course analysis of BMDM phagosomes and how phagosome fate is regulated by the receptors triggered for phagocytosis.
2015-09-10 | PXD000772 | Pride
Project description:Chronic Obstructive Pulmonary Diseases (COPD) is the third leading cause of death worldwide with no curative therapy available. A novel non-canonical Notch ligand, DNER, has been identified in a GWAS to correlate with disease severity, but its function and contribution to COPD is completely unknown. DNER localization and expression was determined in COPD patients and 6 month cigarette smoke (CS)-exposed mice. Microarray and GSEA of M1 and M2 bone marrow-derived macrophages (BMDM) from wild type (WT) and Dner deficient mice were performed. IFNγ levels and Notch activation were evaluated in 2 month CS-exposed WT and Dner deficient mice. Notch and NFκB pathways were evaluated by qPCR and Western Blot in BMDM. DNER was increased in the lung of COPD patients and localized to macrophages in human and murine lung tissue. Upon pro-inflammatory conditions, WT BMDM and human macrophages exhibited increased Dner levels. Interestingly, IFNγ responses were abrogated in Dner deficient pro-inflammatory macrophages both in vitro and in vivo. LPS treated Dner deficient BMDM failed to trigger NFκB and Notch signalling cascades evidenced by the absence of nuclear active forms. We provide the first molecular and functional insights into DNER, a novel Notch ligand that controls IFNγ secretion in lung recruited pro-inflammatory macrophages.
2019-03-19 | GSE119257 | GEO
Project description:Interferon regulatory factor 2 binding protein 2 (Irf2bp2) is a corepressor of Irf2 that suppresses inflammatory gene expression and promotes the M2 macrophage phenotype in bone marrow derived macrophages (BMDM). Loss of Irf2bp2 in male macrophages promotes an inflammatory phenotype. Here, we compared the expression profile of female BMDM to their male counterparts to identify genes differentially affected by the loss of Irf2bp2 by sex in primary macrophages cultured under basal conditions.
2024-09-01 | E-MTAB-14166 | biostudies-arrayexpress