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DNA methylome signature in rheumatoid arthritis

ABSTRACT: Objectives: Epigenetics can influence disease susceptibility and severity. While DNA methylation of individual genes has been explored in autoimmunity, no unbiased systematic analyses have been reported. Therefore, a genome-wide evaluation of DNA methylation loci in fibroblast-like synoviocytes (FLS) isolated from the site of disease in rheumatoid arthritis (RA) was performed. Methods: Genomic DNA was isolated from six RA and five osteoarthritis (OA) FLS lines and evaluated using the Illumina HumanMethylation450 chip. Cluster analysis of data was performed and corrected using Benjamini–Hochberg adjustment for multiple comparisons. Methylation was confirmed by pyrosequencing and gene expression was determined by qPCR. Pathway analysis was performed using the Kyoto Encyclopedia of Genes and Genomes. Results: RA and control FLS segregated based on DNA methylation, with 1859 differentially methylated loci. Hypomethylated loci were identified in key genes relevant to RA, such as CHI3L1, CASP1, STAT3, MAP3K5, MEFV and WISP3. Hypermethylation was also observed, including TGFBR2 and FOXO1. Hypomethylation of individual genes was associated with increased gene expression. Grouped analysis identified 207 hypermethylated or hypomethylated genes with multiple differentially methylated loci, including COL1A1, MEFV and TNF. Hypomethylation was increased in multiple pathways related to cell migration, including focal adhesion, cell adhesion, transendothelial migration and extracellular matrix interactions. Confirmatory studies with OA and normal FLS also demonstrated segregation of RA from control FLS based on methylation pattern. Conclusions: Differentially methylated genes could alter FLS gene expression and contribute to the pathogenesis of RA. DNA methylation of critical genes suggests that RA FLS are imprinted and implicate epigenetic contributions to inflammatory arthritis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE46364 | GEO | 2013/04/25

SECONDARY ACCESSION(S): PRJNA198809

REPOSITORIES: GEO

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Project description:Objectives: Epigenetics can influence disease susceptibility and severity. While DNA methylation of individual genes has been explored in autoimmunity, no unbiased systematic analyses have been reported. Therefore, a genome-wide evaluation of DNA methylation loci in fibroblast-like synoviocytes (FLS) isolated from the site of disease in rheumatoid arthritis (RA) was performed. Methods: Genomic DNA was isolated from six RA and five osteoarthritis (OA) FLS lines and evaluated using the Illumina HumanMethylation450 chip. Cluster analysis of data was performed and corrected using Benjamini–Hochberg adjustment for multiple comparisons. Methylation was confirmed by pyrosequencing and gene expression was determined by qPCR. Pathway analysis was performed using the Kyoto Encyclopedia of Genes and Genomes. Results: RA and control FLS segregated based on DNA methylation, with 1859 differentially methylated loci. Hypomethylated loci were identified in key genes relevant to RA, such as CHI3L1, CASP1, STAT3, MAP3K5, MEFV and WISP3. Hypermethylation was also observed, including TGFBR2 and FOXO1. Hypomethylation of individual genes was associated with increased gene expression. Grouped analysis identified 207 hypermethylated or hypomethylated genes with multiple differentially methylated loci, including COL1A1, MEFV and TNF. Hypomethylation was increased in multiple pathways related to cell migration, including focal adhesion, cell adhesion, transendothelial migration and extracellular matrix interactions. Confirmatory studies with OA and normal FLS also demonstrated segregation of RA from control FLS based on methylation pattern. Conclusions: Differentially methylated genes could alter FLS gene expression and contribute to the pathogenesis of RA. DNA methylation of critical genes suggests that RA FLS are imprinted and implicate epigenetic contributions to inflammatory arthritis. Fibroblast-like synoviocyte cell-lines from osteoarthritis (OA) and rheumatoid arthritis (RA) patients.

Project description:Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints involved with genetic and epigenetic aberrant. Recent evidence found more and more importance of the epigenetic contribution, especially the DNA methylation, to the pathogenesis of rheumatoid arthritis. To understand the extent and nature of dysregulated DNA methylation in rheumatoid arthritis T cells, we performed a genome-wide DNA methylation study in CD4+ T cells in 12 rheumatoid arthritis patients compared to 12 matched normal healthy controls. [Methods and Result] Cytosine methylation status was quantified with Illumina methylation 450K microarray (HM450K, 485512 CpG sites). We identified 810 hypomethylated and 392 hypermethylated CG sites in RA CD4+ T cells compared to normal controls, representing 383 and 785 genes hypermethylated and hypomethylated in RA patients (P<3.4*10-7). Cluster analysis based on significantly differential methylated loci showed distinct separation between RA and normal controls. Gene ontology analysis showed alternative splicing (P=1.2*10-7, FDR) and phosphoprotein (1.7*10-2, FDR) were significantly aberrant in RA patients, indicating the abnormal of transcript alternative splicing and protein modification mediated by DNA methylation might play important role in the pathogenesis of rheumatoid arthritis. What’s more, the result showed human leukocyte antigen (HLA) region was frequently hypomethylated in RA patients, including HLA-DRB6, HLA-DQA1 and HLA-E, however, HLA-DQB1 showed different methylation profiles with significant hypermethylation in CpG island region and hypomethylation in CpG shelf region. Outsite of the MHC region, the most hypermethylated genes in RA included HDAC4, NXN, TBCD and TMEM61 while the most significant hypomethylated genes included ITIH3, TCN2, PRDM16, SLC1A5 and GALNT9. [Conclusion] Genome-wide DNA methylation patterns revealed significant DNA methylation change in CD4+ T cells from patients with rheumatoid arthritis. 12 rheumatoid arthritis and 12 matched health individuals

Project description:Rheumatoid synoviocytes, which consist of fibroblast-like synoviocytes (FLS) and synovial macrophages (SM), are crucial for the progression of rheumatoid arthritis (RA). Particularly, FLS of RA patients (RA-FLS) exhibit invasive characteristics reminiscent of cancer cells, destroying cartilage and bone, although it remains unresolved how RA-FLS exhibit invasive phenotype. RA-FLS and SM originate differently from mesenchymal and myeloid cells, respectively, but share many pathologic functions. However, the molecular signatures and biological networks representing the distinct and shared features of the two cell types are unknown. Presently, we performed global transcriptome profiling of FLS and SM obtained from RA and osteoarthritis patients. By comparing the transcriptomes, we identified distinct molecular signatures and cellular processes defining invasiveness of RA-FLS and pro-inflammatory properties of RA synovial macrophages (RA-SM), respectively. Interestingly, under interleukin1β-stimulated condition, RA-FLS newly acquired pro-inflammatory signature mimicking RA-SM without losing invasive properties. We next reconstructed a network model that delineates the shared, RA-FLS-dominant (invasive), and RA-SM-dominant (inflammatory) processes. From the network model, we selected 13 genes, including POSTN and TWIST1, as novel regulator candidates responsible for FLS invasiveness. Of note, POSTN and TWIST1 expressions were elevated in independent RA-FLS and were further instigated by interleukin1β. In vitro functional assays demonstrated the requirement of POSTN and TWIST1 for migration and invasion of RA-FLS stimulated with interleukin1β. Taken together, our systems approach to rheumatoid synovitis provides a basis for identifying novel regulators responsible for pathological features of RA-FLS and RA-SM, demonstrating how a certain type of cells acquires functional redundancy under chronic inflammatory conditions. To identify molecular signatures of FLS and MLS in RA joints, we isolated FLS from synovial tissues of RA and osteoarthritis (OA) patients, obtained synovial macrophages from synovial fluid of RA patients, and differentiated control macrophages from peripheral blood of healthy subjects. Also, we stimulated FLS with IL1β, and then analyzed gene expression profiles of both IL1β-stimulated RA-FLS and OA-FLS

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DNA methylome signature in rheumatoid arthritis

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