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Epigenetic Regulation of Cyclooxygenase-2 by methylation of c8orf4 in Pulmonary Fibrosis

Evans, IC; Barnes, JL; Garner, IM; Pearce, DR; Maher, TM; Shi-Wen, X; Renzoni, EA; ... McAnulty, RJ; + view all (2016) Epigenetic Regulation of Cyclooxygenase-2 by methylation of c8orf4 in Pulmonary Fibrosis. Clinical Science , 130 (8) pp. 575-586. 10.1042/CS20150697. Green open access

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Abstract

Fibroblasts derived from the lungs of patients with idiopathic pulmonary fibrosis and systemic sclerosis produce low levels of prostaglandin E2, due to a limited capacity to up-regulate cyclooxygenase-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 cyclooxygenase-2 mRNA expression observed in fibrotic lung fibroblasts is regulated epigenetically. The DNA methylation inhibitor, 5 Aza-2'-deoxycytidine restored cyclooxygenase-2 mRNA expression by fibrotic lung fibroblasts dose dependently. Functionally, this resulted in normalization of fibroblast phenotype in terms of prostaglandin E2 production, collagen mRNA expression and sensitivity to apoptosis. Cyclooxygenase-2 methylation assessed by bisulphite 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, c8orf4, which is hypermethylated and down-regulated in fibrotic fibroblasts compared with controls. siRNA knock-down of c8orf4 in control fibroblasts down-regulated cyclooxygenase-2 and prostaglandin E2 production generating a phenotype similar to that observed in fibrotic lung fibroblasts. Chromatin immunoprecipitation demonstrated that c8orf4 regulates cyclooxygenase-2 expression in lung fibroblasts through binding of the proximal promoter.We conclude that the decreased capacity of fibrotic lung fibroblasts to up-regulate cyclooxygenase-2 expression and cyclooxygenase-2 derived prostaglandin E2 synthesis is due to an indirect epigenetic mechanism involving hypermethylation of the transcriptional regulator, c8orf4.

Type: Article
Title: Epigenetic Regulation of Cyclooxygenase-2 by methylation of c8orf4 in Pulmonary Fibrosis
Open access status: An open access version is available from UCL Discovery
DOI: 10.1042/CS20150697
Publisher version: http://dx.doi.org/10.1042/CS20150697
Language: English
Additional information: © 2016 The Author(s). This is an open access article published by Portland Press Limited and distributed under the Creative Commons Attribution License 3.0.
Keywords: cyclooxygenase-2, DNA methylation, fibroblast, idiopathic pulmonary fibrosis, prostaglandin E2, systemic sclerosis.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL EGA Institute for Womens Health > Womens Cancer
URI: https://discovery.ucl.ac.uk/id/eprint/1473905
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