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NOD2- and disease-specific gene expression profiles of peripheral blood mononuclear cells from Crohn’s disease patients

ABSTRACT: Employing microarray assays, a total of 267 genes were identified that were significantly up- or downregulated in PBMCs of WT-NOD2 patients, compared to healthy donors after challenge with vitamin D (+/-D) and/or a combination (+/-LP) of LPS (lipopolysaccharide) and PGN (peptidoglycan) (p < 0.05; threshold: ≥ 2-fold change). For further analysis by real-time PCR, 12 genes with known impact on inflammation and immunity were selected that fulfilled predefined expression criteria. In a larger cohort of patients and controls, a disease-associated expression pattern, with higher transcript levels in vitamin D-treated PBMCs from 5 patients, was observed for three of these genes, CLEC5A (p < 0.030), lysozyme (LYZ; p < 0.047) and TREM1 (p < 0.023). Six genes were found to be expressed in a NOD2- dependent manner (CD101, p < 0.002; CLEC5A, p < 0.020; CXCL5, p < 0.009; IL-24, p < 0.044; ITGB2, p < 0.041; LYZ, p < 0.042). Interestingly, the highest transcript levels were observed in patients with heterozygous NOD2 mutations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE110186 | GEO | 2018/04/03

REPOSITORIES: GEO

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CLEC5A and its impact on early macrophage-mediated inflammation in early progression of COPD

Project description:Methods: This study analyzed lung tissue sequencing data from early-stage COPD patients (GSE47460) and smoke-exposed mice. We employed Weighted Gene Co-Expression Network Analysis (WGCNA) and machine learning to identify potential pathogenic genes. Further analyses included single-cell sequencing from mice and COPD patients to identify gene expression in specific cell subgroups. Cell-chat and pseudo-temporal analyses were conducted, with findings validated in smoke-exposed mice. Additionally, Mendelian randomization (MR) was utilized to verify the relationship between candidate genes and lung function/COPD. Lastly, functional validation was performed in vitro in cell cultures. Results: "Machine learning analysis of 30 differentially expressed genes pinpointed 8 key genes, with CLEC5A identified as a potential pathogenic factor in early COPD. Bioinformatics suggested CLEC5A's role in macrophage-mediated inflammation in COPD. Two-sample Mendelian randomization linked CLEC5A SNPs with FEV1, FEV1/FVC, and emphysema/chronic bronchitis. In vitro, CLEC5A knockdown reduced inflammatory markers in macrophages. Conclusion: Our study identifies CLEC5A as a pivotal gene in early-stage COPD, contributing to its pathogenesis through pro-inflammatory mechanisms. This discovery offers insights for early diagnosis and treatment strategies in COPD, highlighting CLEC5A as a target for further research.

2024-07-21 | GSE255319 | GEO

Expression analysis of BM cells of ASXL-MT induced MDS mice

Project description:Recurrent mutations in ASXL1 are found in various hematological malignancies and are associated with poor prognosis. In particular, ASXL1 mutations are frequently found in patients with hematological malignancies associated with myelodysplasia including myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia. Although loss-of-function ASXL1 mutations promote myeloid transformation, a large subset of ASXL1 mutations is thought to result in stable truncation of ASXL1. Here we demonstrate that C-terminal truncating ASXL1 mutations (ASXL1-MT) inhibit myeloid differentiation and induce MDS-like disease in mice, displaying all the features of human MDS including multi-lineage myelodysplasia, pancytopenia and occasional progression to overt leukemia. Concerning the molecular mechanisms, ASXL1-MT derepressed expression of Hoxa9 and miR-125a through inhibiting PRC2-mediated methylation of H3K27. miR-125a targeted expression of a surface receptor Clec5a, which was found to supports for myeloid differentiation. In addition, HOXA9 expression was high in MDS patients with ASXL1 mutations while Clec5a expression was generally low in MDS patients. Thus, ASXL1-MT induced MDS-like disease in mice via derepression of Hoxa9 and miR-125a, and Clec5a downregulation. Our data provide evidence for a novel axis of MDS pathogenesis (ASXL1 mutations-upregulation of HoxA9 and miR-125a-downregulation of Clec5a) and implicate both ASXL1 mutants and miR-125a as therapeutic targets in MDS.

2013-07-31 | GSE49118 | GEO

Expression analysis of 32Dcl3 cells expressing ASXL-MT in the presence of IL-3 or G-CSF

2013-07-31 | GSE49117 | GEO

NOD2 and human ileal gene expression

Project description:Profiling of ileal mucosal gene expression in Chron's disease patients with and without NOD2 risk alleles; through microarray analyses it was discovered that 18 genes related to lymphocyte and phagocyte activation recuitment were upregulated in affected ileum in NOD2R patients as compared to ileum in NOD2s (no risk alleles) patients, thus supporting the concept that NOD2 risk alleles contribute to impaired regulation of inflammation in the ileum.

2010-01-01 | GSE17594 | GEO

Comprehensive circular RNA expression profiling and competitive endogenous RNAs regulatory networks in distal cholangiocarcinoma

Project description:To explore the differentially expressed (DE) circular (circ)RNAs, competing endogenous RNAs networks, and potential biomarkers in distal cholangiocarcinoma (dCCA), using microarray analysis, a comprehensive circRNA expression profiling was constructed with six paired dCCA tumor and adjacent normal samples. A total of 171 DE circRNAs were identified. Three upregulated (hsa_circ_0060144, hsa_circ_0008274, and hsa_circ_0000673) and two downregulated circRNAs (hsa_circ_0139402 and hsa_circ_0001714) were validated with RT-qPCR in 40 dCCA patients. Among them, hsa_circ_0000673 had an idea prognostic efficiency (AUC=0.85, p<0.01) and high level of hsa_circ_0000673 was associated with late tumor stage (p<0.01), poor histodifferentiation (p=0.041), and residual tumor (p=0.044). Gene ontology analysis of the host genes of 171 DE circRNAs showed that “response to nutrient”, “adherens junction”, and “cell adhesion molecule binding” were mainly enriched in terms of biological process, cellular component, and molecular functions respectively. Nine target micro(mi)RNAs of the five DE circRNAs were screened out and enriched in cancer associated pathways. Thereafter, 188 DE mRNAs were predicted as target genes of the nine miRNAs. Finally, protein-protein interaction networks were constructed and 20 hubgenes were identified. This research provided a landscape of DE circRNAs in dCCA, constructed circRNA-miRNA-mRNA regulating networks, and identified hsa_circ_0000673 as a potential biomarker and target for treating dCCA.

2020-12-31 | GSE148561 | GEO

Myeloid-stromal subtypes reveal NOD2-mediated Crohn's and rescue pathways

Project description:Crohn’s disease (CD) is a chronic inflammatory intestinal disease, often characterized by aberrant healing and stricturing complications. Mechanisms underlying NOD2-pathogenicity and salvage pathways in anti-TNF and refractory patients remain largely uncharacterized. Here we show that loss of NOD2 function leads to aberrant activated fibroblast and macrophage homeostasis through the upregulation of a pathogenic signature, and propose new precision therapeutic approaches involving gp130 blockade for select CD patients, to potentially supplement anti-TNF therapy

2021-03-05 | GSE150498 | GEO

Transcriptome of vitamin D3 bolus supplementation in a cohort of 25 individuals

Project description:In this study, we analyse the in-vivo modulation of the transcriptome of human PBMCs by a bolus of vitamin D3 (80,000 IU) after 24 hours.

2024-03-11 | GSE260981 | GEO

FAIRE-seq in PBMCs

Project description:Three independent repeats of FAIRE-seq from PBMCs obtained before and 1 and 2 days after an oral dose of 2,000 µg (80,000 IU) of vitamin D3

2018-04-09 | GSE106162 | GEO

Vitamin D status associates with skeletal muscle loss after anterior cruciate ligament reconstruction.

Project description:BACKGROUND. Although 25-hydroxyvitamin D (25(OH)D) concentrations ≥30ng/mL are known to reduce injury risk and boost strength, the influence on anterior cruciate ligament reconstruction (ACLR) outcomes remains unexamined. This study aimed to define the vitamin D signaling response to ACLR, assess the relationship between vitamin D status and muscle fiber cross-sectional area (CSA) and bone density outcomes, and discover vitamin D receptor (VDR) targets post-ACLR. METHODS. 21 young, healthy, physically active participants with recent ACL tears were enrolled (62% female; 17.8 ± 3.2 yr, BMI: 26.0 ± 3.5 kg/m2). Data were collected through blood samples, vastus lateralis biopsies, DXA bone density measurements, and isokinetic dynamometer measures at baseline, 1 week, 4 months, and 6 months post-ACLR. The biopsies facilitated CSA, western blot, RNA-seq, and VDR ChIP-seq analyses. RESULTS. ACLR surgery led to decreased circulating bioactive vitamin D and increased VDR and activating enzyme expression in skeletal muscle one week post-operation. Participants with <30 ng/mL 25(OH)D levels (n=13) displayed more significant quadriceps fiber CSA loss one week and 4 months post-ACLR than those with ≥30 ng/mL (n=8; p<0.01 for post-hoc comparisons; p=0.041 for time x vitamin D status interaction). RNA-seq and ChIP-seq data integration revealed genes associated with energy metabolism and skeletal muscle recovery, potentially mediating the impact of vitamin D status on ACLR recovery. No difference in bone mineral density (BMD) losses between groups was observed.

2023-12-31 | GSE243777 | GEO

Pluripotent stem cell models of Blau syndrome reveal an IFN-<gamma>-dependent inflammatory response in macrophages

Project description:Background: Blau syndrome, or early-onset sarcoidosis, is a juvenile-onset systemic granulomatosis associated with a mutation in Nucleotide-binding oligomerization domain 2 (NOD2). The underlying mechanisms of Blau syndrome leading to autoinflammation are still unclear, and there is currently no effective specific treatment for Blau syndrome. Objectives: To elucidate the mechanisms of autoinflammation in Blau syndrome, we sought to clarify the relation between disease associated-mutant NOD2 and the inflammatory response in human samples. Methods: Blau syndrome-specific induced pluripotent stem cells (iPSCs) lines were established. To precisely evaluate the in vitro phenotype of iPSC-derived cells, the disease-associated NOD2 mutation of iPSCs was corrected using a CRISPR/Cas9 system. We also introduced the same NOD2 mutation into a control iPSC line. These isogenic iPSCs were then differentiated into monocytic cell lineages, and the status of NF-κB pathway and proinflammatory cytokine secretion were investigated. Results: We focused on the signals that upregulate the expression of NOD2, especially IFN-γ signaling. IFN-γ treatment of NOD2-mutant macrophages induced ligand-independent NF-κB activation and proinflammatory cytokine production. IFN-γ treatment acted as a priming signal through the up-regulation of NOD2 protein and recruitment of NOD2 on the basement membrane. Conversely, the production of proinflammatory cytokines by MDP, a ligand of NOD2, was decreased in mutant macrophages. Conclusions: Our data support the significance of ligand-independent autoinflammation in the pathophysiology of Blau syndrome. Our comprehensive isogenic disease-specific iPSC panel provides a useful platform for probing therapeutic and diagnostic clues for the treatment of Blau syndrome patients.

2018-01-24 | GSE98454 | GEO

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