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We identified a profibrotic lung phenotype in aging mice characterized by an increase in the number of fibroblasts lacking the expression of thymocyte differentiation antigen 1 (Thy-1) and an increase in transforming growth factor (TGF)-\u03b21 expression. It has been shown that Thy-1 expression can be epigenetically modified. Lung fibroblasts (PLFs) were treated with TGF-\u03b21 \u00b1 DNA methyltransferase (DNMT) inhibitor 5-aza-2\u2032-deoxycytidine (5-AZA) and analyzed for Thy-1 gene and protein expression, DNMT protein expression, and activity. \u03b1-Smooth muscle actin (\u03b1-SMA) and collagen type 1 (Col1A1) gene and protein expression was assessed. PLFs were transfected with DNMT1 silencing RNA \u00b1 TGF-\u03b21. TGF-\u03b21 inhibited Thy-1 gene and protein expression in PLFs, and cotreatment with 5-AZA ameliorated this effect and appeared to inhibit DNMT1 activation. TGF-\u03b21 induced Thy-1 promoter methylation as assessed by quantitative methyl PCR. Treatment with 5-AZA attenuated TGF-\u03b21-induced Col1A1 gene and protein expression and \u03b1-SMA gene expression (but not \u03b1-SMA protein expression). Inhibiting DNMT1 with silencing RNA attenuated TGF-\u03b21-induced DNMT activity and its downstream suppression of Thy-1 mRNA and protein expression as well as inhibited \u03b1-SMA mRNA and Col1A1 mRNA and protein expression, and showed a decreased trend in Thy-1 promoter methylation. Immunofluorescence for \u03b1-SMA suggested that 5-AZA inhibited stress fiber formation. These findings suggest that TGF-\u03b21 epigenetically regulates lung fibroblast phenotype through methylation of the Thy-1 promoter. Targeted inhibition of DNMT in the right clinical context might prevent fibroblast to myofibroblast transdifferentiation and collagen deposition, which in turn could prevent fibrogenesis in the lung and other organs. <\/jats:p>","DOI":"10.1152\/ajpcell.00086.2015","type":"journal-article","created":{"date-parts":[[2015,9,3]],"date-time":"2015-09-03T03:03:32Z","timestamp":1441249412000},"page":"C616-C626","source":"Crossref","is-referenced-by-count":62,"title":["TGF-\u03b21 epigenetically modifies Thy-1 expression in primary lung fibroblasts"],"prefix":"10.1152","volume":"309","author":[{"given":"Wendy A.","family":"Neveu","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen T.","family":"Mills","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical 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