{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,11]],"date-time":"2026-11-11T06:22:48Z","timestamp":1794378168322,"version":"4.9.0"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,5,9]],"date-time":"2018-05-09T00:00:00Z","timestamp":1525824000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,5,9]],"date-time":"2018-05-09T00:00:00Z","timestamp":1525824000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>DNA methylation is an important epigenetic modification that is known to be altered in rheumatoid arthritis synovial fibroblasts (RASF). Here, we compared the status of promoter DNA methylation of SF from patients with very early RA with SF from patients with resolving arthritis, fully established RA and from non-arthritic patients. DNA was hybridized to Infinium Human methylation 450k and 850k arrays and differential methylated genes and pathways were identified. We could identify a significant number of CpG sites that differed between the SF of different disease stages, showing that epigenetic changes in SF occur early in RA development. Principal component analysis confirmed that the different groups of SF were separated according to their DNA methylation state. Furthermore, pathway analysis showed that important functional pathways were altered in both very early and late RASF. By focusing our analysis on CpG sites in CpG islands within promoters, we identified genes that have significant hypermethylated promoters in very early RASF. Our data show that changes in DNA methylation differ in RASF compared to other forms of arthritis and occur at a very early, clinically yet unspecific stage of disease. The identified differential methylated genes might become valuable prognostic biomarkers for RA development.<\/jats:p>","DOI":"10.1038\/s41598-018-24240-2","type":"journal-article","created":{"date-parts":[[2018,5,3]],"date-time":"2018-05-03T11:21:14Z","timestamp":1525346474000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":78,"title":["Analysis of early changes in DNA methylation in synovial fibroblasts of RA patients before diagnosis"],"prefix":"10.1038","volume":"8","author":[{"given":"Emmanuel","family":"Karouzakis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karim","family":"Raza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2802-7638","authenticated-orcid":false,"given":"Christoph","family":"Kolling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6924-6402","authenticated-orcid":false,"given":"Christopher D.","family":"Buckley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steffen","family":"Gay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Filer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Ospelt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,5,9]]},"reference":[{"key":"24240_CR1","doi-asserted-by":"publisher","first-page":"2741","DOI":"10.1002\/art.11223","volume":"48","author":"S Rantapaa-Dahlqvist","year":"2003","unstructured":"Rantapaa-Dahlqvist, S. et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis and rheumatism 48, 2741\u20132749, https:\/\/doi.org\/10.1002\/art.11223 (2003).","journal-title":"Arthritis and rheumatism"},{"key":"24240_CR2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11849","volume":"7","author":"R Ai","year":"2016","unstructured":"Ai, R. et al. Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes. Nat Commun 7, 11849, https:\/\/doi.org\/10.1038\/ncomms11849 (2016).","journal-title":"Nat Commun"},{"key":"24240_CR3","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.jaut.2012.12.005","volume":"41","author":"L de la Rica","year":"2013","unstructured":"de la Rica, L. et al. Identification of novel markers in rheumatoid arthritis through integrated analysis of DNA methylation and microRNA expression. J Autoimmun 41, 6\u201316, https:\/\/doi.org\/10.1016\/j.jaut.2012.12.005 (2013).","journal-title":"J Autoimmun"},{"key":"24240_CR4","doi-asserted-by":"publisher","first-page":"3613","DOI":"10.1002\/art.25018","volume":"60","author":"E Karouzakis","year":"2009","unstructured":"Karouzakis, E., Gay, R. E., Michel, B. A., Gay, S. & Neidhart, M. DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum 60, 3613\u20133622, https:\/\/doi.org\/10.1002\/art.25018 (2009).","journal-title":"Arthritis Rheum"},{"key":"24240_CR5","doi-asserted-by":"publisher","DOI":"10.1186\/gm444","volume":"5","author":"JW Whitaker","year":"2013","unstructured":"Whitaker, J. W. et al. An imprinted rheumatoid arthritis methylome signature reflects pathogenic phenotype. Genome Med 5, 40, https:\/\/doi.org\/10.1186\/gm444 (2013).","journal-title":"Genome Med"},{"key":"24240_CR6","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.ejcb.2016.06.003","volume":"95","author":"C Dowson","year":"2016","unstructured":"Dowson, C. & O\u2019Reilly, S. DNA methylation in fibrosis. Eur J Cell Biol 95, 323\u2013330, https:\/\/doi.org\/10.1016\/j.ejcb.2016.06.003 (2016).","journal-title":"Eur J Cell Biol"},{"key":"24240_CR7","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1038\/nature12750","volume":"502","author":"RM Kohli","year":"2013","unstructured":"Kohli, R. M. & Zhang, Y. TET enzymes, TDG and the dynamics of DNA demethylation. Nature 502, 472\u2013479, https:\/\/doi.org\/10.1038\/nature12750 (2013).","journal-title":"Nature"},{"key":"24240_CR8","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1038\/sj.gene.6364400","volume":"8","author":"CL Galligan","year":"2007","unstructured":"Galligan, C. L., Baig, E., Bykerk, V., Keystone, E. C. & Fish, E. N. Distinctive gene expression signatures in rheumatoid arthritis synovial tissue fibroblast cells: correlates with disease activity. Genes Immun 8, 480\u2013491, https:\/\/doi.org\/10.1038\/sj.gene.6364400 (2007).","journal-title":"Genes Immun"},{"key":"24240_CR9","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1136\/annrheumdis-2011-200281","volume":"71","author":"MJ Del Rey","year":"2012","unstructured":"Del Rey, M. J. et al. Transcriptome analysis reveals specific changes in osteoarthritis synovial fibroblasts. Ann Rheum Dis 71, 275\u2013280, https:\/\/doi.org\/10.1136\/annrheumdis-2011-200281 (2012).","journal-title":"Ann Rheum Dis"},{"key":"24240_CR10","doi-asserted-by":"publisher","first-page":"R784","DOI":"10.1186\/ar1733","volume":"7","author":"K Raza","year":"2005","unstructured":"Raza, K. et al. Early rheumatoid arthritis is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis research & therapy 7, R784\u2013795, https:\/\/doi.org\/10.1186\/ar1733 (2005).","journal-title":"Arthritis research & therapy"},{"key":"24240_CR11","doi-asserted-by":"publisher","first-page":"763","DOI":"10.1136\/annrheumdis-2014-206921","volume":"75","author":"L Yeo","year":"2016","unstructured":"Yeo, L. et al. Expression of chemokines CXCL4 and CXCL7 by synovial macrophages defines an early stage of rheumatoid arthritis. Ann Rheum Dis 75, 763\u2013771, https:\/\/doi.org\/10.1136\/annrheumdis-2014-206921 (2016).","journal-title":"Ann Rheum Dis"},{"key":"24240_CR12","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s13075-016-0915-3","volume":"18","author":"M Juarez","year":"2016","unstructured":"Juarez, M. et al. DKK1 expression by synovial fibroblasts in very early rheumatoid arthritis associates with lymphocyte adhesion in an in vitro flow co-culture system. Arthritis research & therapy 18, 14, https:\/\/doi.org\/10.1186\/s13075-016-0915-3 (2016).","journal-title":"Arthritis research & therapy"},{"key":"24240_CR13","doi-asserted-by":"publisher","first-page":"1978","DOI":"10.1002\/art.39123","volume":"67","author":"R Ai","year":"2015","unstructured":"Ai, R. et al. DNA Methylome Signature in Synoviocytes From Patients With Early Rheumatoid Arthritis Compared to Synoviocytes From Patients With Longstanding Rheumatoid Arthritis. Arthritis & rheumatology 67, 1978\u20131980, https:\/\/doi.org\/10.1002\/art.39123 (2015).","journal-title":"Arthritis & rheumatology"},{"key":"24240_CR14","doi-asserted-by":"publisher","unstructured":"Ntougkos, E. et al. Genomic Responses of Mouse Synovial Fibroblasts During Tumor Necrosis Factor-Driven Arthritogenesis Greatly Mimic Those in Human Rheumatoid Arthritis. 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