{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T12:59:35Z","timestamp":1791291575502,"version":"4.3.0"},"reference-count":33,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2006,6,26]],"date-time":"2006-06-26T00:00:00Z","timestamp":1151280000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Arthritis &amp; Rheumatism"],"published-print":{"date-parts":[[2006,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Scleroderma (systemic sclerosis; SSc) is an autoimmune disease characterized by vasculopathy and widespread organ fibrosis. Altered fibroblast function, both in vivo and in vitro, is well documented and illustrated by augmented synthesis and deposition of extracellular matrix proteins. We undertook this study to investigate the possibility that epigenetic mechanisms mediate the emergence and persistence of the altered SSc fibroblast phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The effects of DNA methyltransferase and histone deacetylase inhibitors on collagen expression and the level of epigenetic mediators in fibroblasts were examined. The effects of transient transfection of SSc fibroblasts with <jats:italic>FLI1<\/jats:italic> gene and normal cells with <jats:italic>FLI1<\/jats:italic> antisense construct on collagen expression were determined. The methylation status of the <jats:italic>FLI1<\/jats:italic> promoter was tested in cultured cells and in SSc and normal skin biopsy specimens.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Increased levels of epigenetic mediators in SSc fibroblasts were noted. The addition of epigenetic inhibitors to cell cultures normalized collagen expression in SSc fibroblasts. The augmented collagen synthesis by SSc fibroblasts was linked to epigenetic repression of the collagen suppressor gene <jats:italic>FLI1<\/jats:italic>. Heavy methylation of the CpG islands in the <jats:italic>FLI1<\/jats:italic> promoter region was demonstrated in SSc fibroblasts and skin biopsy specimens.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The results of this study indicate that epigenetic mechanisms may mediate the fibrotic manifestations of SSc. The signal transduction leading to the SSc fibrotic phenotype appears to converge on DNA methylation and histone deacetylation at the <jats:italic>FLI1 g<\/jats:italic>ene.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.21948","type":"journal-article","created":{"date-parts":[[2006,6,27]],"date-time":"2006-06-27T00:05:59Z","timestamp":1151366759000},"page":"2271-2279","source":"Crossref","is-referenced-by-count":326,"title":["Association between enhanced type I collagen expression and epigenetic repression of the <i>FLI1<\/i> gene in scleroderma fibroblasts"],"prefix":"10.1002","volume":"54","author":[{"given":"Youngqing","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pan\u2010Sheng","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bashar","family":"Kahaleh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,6,27]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI107827"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1568-9972(03)00005-3"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.55.3.451-458.1991"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra023075"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/bfgp\/2.3.234"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0959-437X(93)90027-M"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780230510"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M314251200"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207470"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.55.3.451-458.1991"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.062010399"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/art.11157"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M403477200"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63685-1"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M010133200"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bth059"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/18.11.1427"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0174-173X(81)80007-6"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/s001090050216"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117154"},{"key":"e_1_2_6_22_2","first-page":"756","article-title":"Fibroblast heterogeneity in scleroderma: Clq studies","volume":"14","author":"Maxwell DB","year":"1987","journal-title":"J Rheumatol"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0168-9525(97)01219-5"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1089"},{"key":"e_1_2_6_25_2","first-page":"4346","article-title":"Aberrant methylation of the estrogen receptor and E\u2010cadherin 5\u2032CpG islands increases with malignant progression in human breast cancer","volume":"60","author":"Nass SJ","year":"2000","journal-title":"Cancer Res"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1053\/meta.2001.25655"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1136\/gut.47.2.302"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-3835(00)00566-8"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203672"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1177\/153537020222700502"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1204042"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0394-236"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20031675"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(02)00932-4"}],"container-title":["Arthritis &amp; 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