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H3K27me3 regulates macrophage cytokine transcription and impacts on Collagen Induced Arthritis [ATAC-Seq]

ABSTRACT: The role of epigenetic regulation has been introduced in the process of macrophage polarization and the pathogenesis of inflammatory diseases. As a repressive epigenetic marker, tri-methylation of lysine 27 on histone H3 (H3K27me3) was shown to be important for transcriptional gene expression regulation. Here, we comprehensively analysed H3K27me3 binding promoter sequences by ChIP-seq and corresponding genes function by RNA sequencing in two differentially polarized macrophage populations. The results revealed that H3K27me3 binds on the promoter regions of multiple critical cytokine genes and suppressed their transcription, especially in M-CSF derived macrophages but not GM-CSF derived counterparts. The in vivo study results suggested that symptoms of collagen induced arthritis (CIA) mice can be relieved by reversing the loss of H3K27me3 and reducing IL6 parasecretion of macrophages, suggesting that H3K27me3 might act as a switch in the pathological processes of rheumatoid arthritis (RA). Our results may provide a new approach for the treatment of inflammatory and autoimmune disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE188613 | GEO | 2024/11/09

REPOSITORIES: GEO

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H3K27me3 regulates macrophage cytokine transcription and impacts on Collagen Induced Arthritis [RNA-Seq]

Project description:The role of epigenetic regulation has been introduced in the process of macrophage polarization and the pathogenesis of inflammatory diseases. As a repressive epigenetic marker, tri-methylation of lysine 27 on histone H3 (H3K27me3) was shown to be important for transcriptional gene expression regulation. Here, we comprehensively analyzed H3K27me3 binding promoter sequences by ChIP-seq and corresponding genes function by RNA sequencing in two differentially polarized macrophage populations. The results revealed that H3K27me3 binds on the promoter regions of multiple critical cytokine genes and suppressed their transcription, especially in M-CSF derived macrophages but not GM-CSF derived counterparts. The in vivo study results suggested that symptoms of collagen induced arthritis (CIA) mice can be relieved by reversing the loss of H3K27me3 and reducing IL6 parasecretion of macrophages, suggesting that H3K27me3 might act as a switch in the pathological processes of rheumatoid arthritis (RA). Our results may provide a new approach for the treatment of inflammatory and autoimmune disorders.

2022-03-10 | GSE188615 | GEO

H3K27me3 regulates macrophage cytokine transcription and impacts on Collagen Induced Arthritis [ChIP-Seq]

Project description:The role of epigenetic regulation has been introduced in the process of macrophage polarization and the pathogenesis of inflammatory diseases. As a repressive epigenetic marker, tri-methylation of lysine 27 on histone H3 (H3K27me3) was shown to be important for transcriptional gene expression regulation. Here, we comprehensively analysed H3K27me3 binding promoter sequences by ChIP-seq and corresponding genes function by RNA sequencing in two differentially polarized macrophage populations. The results revealed that H3K27me3 binds on the promoter regions of multiple critical cytokine genes and suppressed their transcription, especially in M-CSF derived macrophages but not GM-CSF derived counterparts. The in vivo study results suggested that symptoms of collagen induced arthritis (CIA) mice can be relieved by reversing the loss of H3K27me3 and reducing IL6 parasecretion of macrophages, suggesting that H3K27me3 might act as a switch in the pathological processes of rheumatoid arthritis (RA). Our results may provide a new approach for the treatment of inflammatory and autoimmune disorders.

2024-11-09 | GSE188614 | GEO

Integrated transcriptomic and metabolomic analysis reveals the metabolic programming of GM-CSF-and M-CSF-differentiated mouse macrophages

Project description:Macrophages play a critical role in the inflammatory response and tumor development. Macrophages are primarily divided into pro-inflammatory M1-like and anti-inflammatory M2-like macrophages based on their activation status and functions. In vitro macrophage models could be derived from mouse bone marrow cells stimulated with two types of differentiation factors: GM-CSF (GM-BMDMs) and M-CSF (M-BMDMs), to represent M1-and M2-like macrophages, respectively. Since macrophage differentiation requires coordinated metabolic reprogramming and transcriptional rewiring in order to fulfill their distinct roles, we combined both transcriptome and metabolome analysis, coupled with experimental validation, to gain insight into the metabolic status of GM-and M-BMDMs. The data revealed higher levels of the tricarboxylic acid cycle (TCA cycle), oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and urea and ornithine production from arginine in GM-BMDMs, and a preference for glycolysis, fatty acid storage, bile acid metabolism, and citrulline and nitric oxide (NO) production from arginine in M-BMDMs. Correlation analysis with the proteomic data showed high consistency in the mRNA and protein levels of metabolic genes. Similar results were also obtained when compared to RNA-seq data of human monocyte derived macrophages from the GEO database. Furthermore, canonical macrophage functions such as inflammatory response and phagocytosis were tightly associated with the representative metabolic pathways. In the current study, we identified the core metabolites, metabolic genes, and functional terms of the two distinct mouse macrophage populations. We also distinguished the metabolic influences of the differentiation factors GM-CSF and M-CSF, and wish to provide valuable information for in vitro macrophage studies.

2023-09-19 | MTBLS6502 | MetaboLights

Transcription repressor Bach2 is required for pulmonary surfactant homeostasis and alveolar macrophage function.

Project description:Pulmonary alveolar proteinosis (PAP) results from a dysfunction of alveolar macrophages (AMs), chiefly due to disruptions in the signaling of granulocyte macrophage colony-stimulating factor (GM-CSF). We found that mice deficient for the B lymphoid transcription repressor BTB and CNC homology 2 (Bach2) developed PAP-like accumulation of surfactant proteins in the lungs. Bach2 was expressed in AMs, and Bach2-deficient AMs showed alterations in lipid handling in comparison with wild-type (WT) cells. Although Bach2-deficient AMs showed a normal expression of the genes involved in the GM-CSF signaling, they showed an altered expression of the genes involved in chemotaxis, lipid metabolism, and alternative M2 macrophage activation with increased expression of Ym1 and arginase-1, and the M2 regulator Irf4. Peritoneal Bach2-deficient macrophages showed increased Ym1 expression when stimulated with interleukin-4. More eosinophils were present in the lung and peritoneal cavity of Bach2-deficient mice compared with WT mice. The PAP-like lesions in Bach2-deficient mice were relieved by WT bone marrow transplantation even after their development, confirming the hematopoietic origin of the lesions. These results indicate that Bach2 is required for the functional maturation of AMs and pulmonary homeostasis, independently of the GM-CSF signaling. WT (n=8) and Bach2KO (n=3) AMs. One expreriment was performed.

2014-01-15 | E-GEOD-54050 | biostudies-arrayexpress

Expression of a murine model of Rheumatoid Arthritis with or without Intermittent fasting

Project description:Intermittent fasting (IF) reduces the inflammatory symptoms of Rheumatoid Arthritis (RA); however, its anti-inflammatory underlying molecular mechanisms are unknown. Aim: To investigate the effect of IF on joint inflammatory molecular mechanisms in collagen-induced arthritis (CIA) through DNA microarray and clinical and histopathological evaluations. Methods: CIA was induced in sixteen male DBA/1 mice divided into two groups, one received every other day IF for four weeks. The clinical, histological, and transcriptomic analyses, through DNA microarray, were done to evaluate the effect of IF on joint inflammation and remodeling. Results: CIA mice with IF show lower arthritis incidence and severity. IF also decreased the histological inflammation and joint damage. DNA microarrays dataset revealed 364 overexpressed and 543 subexpressed genes. The highest over- and subexpressed genes were the Ereg and MUPs, respectively. Retinol biosynthesis and the macrophage alternative activation pathways were associated with a positive z-score. Pathways with negative z-scores were related to the inflammatory process, including systemic lupus erythematosus in B cells and osteoarthritis, in which the RA-related genes Cd72, Cd79a, Ifna, Il33, and Bglap2 were found to be decreased. The bioinformatic algorithm identified four central possible regulators: CEBPA, FOXO1, HIF1A, PPARG, and PPARA. In the analysis of diseases and biofunctions, molecular transport, small molecule biochemistry, and lipid and carbohydrate metabolism tended to increase; conversely, organismal injury and abnormalities, inflammatory response, metabolic diseases, cancer, and endocrine, reproductive, gastrointestinal, skeletal, and muscular system disorders, were decreased by IF

2024-10-25 | GSE242986 | GEO

0.1 Terahertz irradiation alleviates rheumatoid arthritis and exerts immunomodulatory effects in CIA mice

Project description:This study investigated the systemic effects of 0.1 THz irradiation on the inflammatory status of rheumatoid arthritis (RA) in the collagen-induced arthritis (CIA) mouse model. It was found that THz irradiation apparently alleviated the symptoms of arthritis in CIA mice, reducing the joint swelling, mitigating the tissue damage and relieving the expression of pro-inflammatory factors (TNF-, IL-6, RANKL and MMPs) in the swollen joint of the CIA mice. Moreover, the reduction of serum inflammatory cytokines levels together with the reduced CD4+ T cell count and the recovered percentage of regulatory T cells (Treg) indicated that THz irradiation exerted a systemic immunoregulatory activity in CIA mice. The blood leukocyte mRNA-seq GO analysis also enriched several biological processes including the differentiation and adhesion of leukocytes, lymphocyte differentiation and T cell activation, providing additional supporting evidence for the immunoregulatory effects of THz.

2024-06-20 | GSE246029 | GEO

Expression data from mouse arthritis tarsal joints

Project description:Pathological bone changes differ considerably between inflammatory arthritic diseases, and most studies have focused on bone erosion. Collagen Induced Arthritis (CIA) is a model for Rheumatoid Arthritis, which, in addition to bone erosion, demonstrates bone formation at the time for clinical manifestations. The objective of this study was to use the CIA model to study bone remodelling by performing a gene expression profiling time-course study on the CIA model.

2015-03-01 | GSE61140 | GEO

Epigenetic regulation of NfatC1 transcription and osteoclastogenesis by nicotinamide phosphoribosyl transferase in the pathogenesis of arthritis

Project description:Nicotinamide phosphoribosyltransferase (NAMPT) functions in NAD synthesis, apoptosis, and inflammation. Dysregulation of NAMPT has been associated with several inflammatory diseases, including rheumatoid arthritis (RA). The purpose of this study was to investigate NAMPT’s role in arthritis using mouse and cellular models. Collagen-induced arthritis (CIA) in DBA/1J Nampt+/- mice was evaluated by ELISA, micro-CT and RNA-sequencing (RNA-seq). In vitro Nampt loss-of-function and gain-of-function studies on osteoclastogenesis were examined by TRAP staining, nascent RNA capture, luciferase reporter assays, and ChIP-PCR. Nampt-deficient mice presented with suppressed inflammatory bone destruction and disease progression in a CIA mouse model. Nampt expression was required for the epigenetic regulation of the Nfatc1 promoter and osteoclastogenesis. Finally, RNA-seq identified 690 differentially expressed genes in whole ankle joints which associated (P<0.05) with Nampt expression and CIA. Selected target was validated by RT-PCR or functional characterization. We have provided evidence that NAMPT functions as a genetic risk factor and a potential therapeutic target to RA.

2019-01-31 | GSE121793 | GEO

Time-course gene expression profiles of the synovial tissues in collagen-induced arthritis

Project description:We observed resolution of inflammatory response in collagen-induced arthritis (CIA) mice. To identify molecular signatures defining resolution of the CIA, we applied microarray analysis for synovial tissues in the CIA mice in 6 (induction), 9 (peak) and 15 weeks (resolution) after immunization. To identify genes related to CIA resolution, we performed the following comparisons of gene expression profiles: peak versus induction phase and resolution versus peak phase. We identified that three genes, Itgb1, Ywhaz and Rps3, are the key regulators for the resolution by measuring degree, betweenness and closeness centrality in reconstructed network based on protein-protein interaction data. To confirm this result, we compared the gene and protein expression level of the three regulators between the two phases of inflammation. Furthermore, we showed that the gene and protein expression level of the three regulators are up-regulated in regulatory T cells and type 2 macrophages than other subtypes of CD4+ T cells and macrophages, and also we examined that recombinant peritoneal macrophages of the three regulators can modulate the expression of pro-inflammatory and anti-inflammatory cytokines. Thus, our findings suggest that those regulators can be employed as therapeutic uses for resolving inflammation

2020-05-19 | GSE99087 | GEO

Expression data from fibroblast-like synoviocytes (FLS) transfected with mimic-miR-23b or mimic-NC

Project description:We found microRNA miR-23b was down-regulated in local inflammatory tissues of autoimmune disease such as RA, SLE and related mouse models such as CIA, lpr, EAE. Re-expression of miR-23b significantly inhibits autoimmune pathogenesis of CIA, Lpr and EAE. To identify potential targets of miR-23b, we use microarray gene-expression analysis to identify transcripts which could be repressed by miR-23b. RA: rheumatoid arthritis, CIA: Collagen-induced arthritis, SLE: systemic lupus erythematosus, EAE: experimental autoimmune encephalomyelitis We tansfected fibroblast-like synoviocytes (FLS) with mimic-miR-23b or mimic-NC.Cells were collected and total RNA was extracted for the Affymetrix GeneChipÂ® Human Genome U133 Plus 2.0 Array

2012-12-19 | E-GEOD-37427 | biostudies-arrayexpress

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