Imperial College London


Faculty of MedicineDepartment of Surgery & Cancer

Research Associate







Institute of Reproductive and Developmental BiologyHammersmith Campus





Publication Type

3 results found

Evans IC, Barnes JL, Garner IM, Pearce DR, Maher TM, Shiwen X, Renzoni EA, Wells AU, Denton CP, Laurent GJ, Abraham DJ, McAnulty RJet al., 2016, Epigenetic regulation of cyclooxygenase-2 by methylation of c8orf4 in pulmonary fibrosis, Clinical Science, Vol: 130, Pages: 575-586, ISSN: 1470-8736

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'-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 in 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.

Journal article

Garner IM, Evans IC, Maher TM, Renzoni EA, Denton CP, Scotton CJ, Abraham DJ, McAnulty RJet al., 2013, Genome-wide analysis identifies multiple genes with altered methylation and expression in IPF and SSc lung fibroblasts, Spring Meeting of the British-Society-for-Matrix-Biology, Publisher: WILEY-BLACKWELL, Pages: A15-A16, ISSN: 0959-9673

Conference paper

Garner IM, Evans IC, Barnes JL, Maher TM, Renzoni EA, Denton CP, Scotton CJ, Abraham DJ, McAnulty RJet al., 2013, Hypomethylation of the TNXB gene contributes to increased expression and deposition of tenascin X in idiopathic pulmonary fibrosis, Spring Meeting of the British-Society-for-Matrix-Biology, Publisher: WILEY-BLACKWELL, Pages: A15-A15, ISSN: 0959-9673

Conference paper

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