3 results found
Evans IC, Barnes JL, Garner IM, et 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.
Garner IM, Evans IC, Maher TM, et 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
Garner IM, Evans IC, Barnes JL, et 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
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