{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T22:22:02Z","timestamp":1776896522882,"version":"3.51.2"},"reference-count":48,"publisher":"Portland Press Ltd.","issue":"8","license":[{"start":{"date-parts":[[2019,7,25]],"date-time":"2019-07-25T00:00:00Z","timestamp":1564012800000},"content-version":"vor","delay-in-days":1234,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,4,1]]},"abstract":"<jats:p>Fibroblasts derived from the lungs of patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc) produce low levels of prostaglandin (PG) E2, due to a limited capacity to up-regulate cyclooxygenase-2 (COX-2). This deficiency contributes functionally to the fibroproliferative state, however the mechanisms responsible are incompletely understood. In the present study, we examined whether the reduced level of COX-2 mRNA expression observed in fibrotic lung fibroblasts is regulated epigenetically. The DNA methylation inhibitor, 5-aza-2\u2032-deoxycytidine (5AZA) restored COX-2 mRNA expression by fibrotic lung fibroblasts dose dependently. Functionally, this resulted in normalization of fibroblast phenotype in terms of PGE2 production, collagen mRNA expression and sensitivity to apoptosis. COX-2 methylation assessed by bisulfite sequencing and methylation microarrays was not different in fibrotic fibroblasts compared with controls. However, further analysis of the methylation array data identified a transcriptional regulator, chromosome 8 open reading frame 4 (thyroid cancer protein 1, TC-1) (c8orf4), which is hypermethylated and down-regulated in fibrotic fibroblasts compared with controls. siRNA knockdown of c8orf4\u00a0in control fibroblasts down-regulated COX-2 and PGE2 production generating a phenotype similar to that observed in fibrotic lung fibroblasts. Chromatin immunoprecipitation demonstrated that c8orf4 regulates COX-2 expression in lung fibroblasts through binding of the proximal promoter. We conclude that the decreased capacity of fibrotic lung fibroblasts to up-regulate COX-2 expression and COX-2-derived PGE2 synthesis is due to an indirect epigenetic mechanism involving hypermethylation of the transcriptional regulator, c8orf4.<\/jats:p>","DOI":"10.1042\/cs20150697","type":"journal-article","created":{"date-parts":[[2016,1,8]],"date-time":"2016-01-08T03:38:58Z","timestamp":1452224338000},"page":"575-586","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":67,"title":["Epigenetic regulation of cyclooxygenase-2 by methylation of c8orf4\u00a0in pulmonary fibrosis"],"prefix":"10.1042","volume":"130","author":[{"given":"Iona\u00a0C.","family":"Evans","sequence":"first","affiliation":[{"name":"UCL Respiratory Centre for Inflammation and Tissue Repair, Rayne Building, University College London, London, WC1E 6JF, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josephine\u00a0L.","family":"Barnes","sequence":"additional","affiliation":[{"name":"UCL Respiratory Centre for Inflammation and Tissue Repair, Rayne Building, University College London, London, WC1E 6JF, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ian\u00a0M.","family":"Garner","sequence":"additional","affiliation":[{"name":"UCL Respiratory Centre for Inflammation and Tissue Repair, Rayne Building, University College London, London, WC1E 6JF, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David\u00a0R.","family":"Pearce","sequence":"additional","affiliation":[{"name":"UCL Respiratory Centre for Inflammation and Tissue Repair, Rayne Building, University College London, London, WC1E 6JF, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toby\u00a0M.","family":"Maher","sequence":"additional","affiliation":[{"name":"UCL Respiratory Centre for Inflammation and Tissue Repair, Rayne Building, University College London, London, WC1E 6JF, U.K."},{"name":"NIHR Biomedical Research Unit & Interstitial Lung Disease Unit, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xu","family":"Shiwen","sequence":"additional","affiliation":[{"name":"Centre for Rheumatology and Connective Tissue Diseases, Royal Free Campus, University College London, London, NW3 2PF, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabetta\u00a0A.","family":"Renzoni","sequence":"additional","affiliation":[{"name":"NIHR Biomedical Research Unit & Interstitial Lung Disease Unit, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Athol\u00a0U.","family":"Wells","sequence":"additional","affiliation":[{"name":"NIHR Biomedical Research Unit & Interstitial Lung Disease Unit, Royal Brompton Hospital, Sydney Street, London, SW3 6NP, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher\u00a0P.","family":"Denton","sequence":"additional","affiliation":[{"name":"Centre for Rheumatology and Connective Tissue Diseases, Royal Free Campus, University College London, London, NW3 2PF, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Geoffrey\u00a0J.","family":"Laurent","sequence":"additional","affiliation":[{"name":"Centre for Cell Therapy and Regenerative Medicine, School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute of Medical Research, Crawley, WA 6009, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David\u00a0J.","family":"Abraham","sequence":"additional","affiliation":[{"name":"Centre for Rheumatology and Connective Tissue Diseases, Royal Free Campus, University College London, London, NW3 2PF, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robin\u00a0J.","family":"McAnulty","sequence":"additional","affiliation":[{"name":"UCL Respiratory Centre for Inflammation and Tissue Repair, Rayne Building, University College London, London, WC1E 6JF, U.K."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2016,3,8]]},"reference":[{"key":"2021113010470637000_B1","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1183\/09031936.00069307","article-title":"Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms?","volume":"30","author":"Maher","year":"2007","journal-title":"Eur. 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