Imperial College London

DrIanGarner

Faculty of MedicineDepartment of Surgery & Cancer

Research Associate
 
 
 
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Contact

 

i.garner

 
 
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Location

 

Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Evans:2016:10.1042/CS20150697,
author = {Evans, IC and Barnes, JL and Garner, IM and Pearce, DR and Maher, TM and Shiwen, X and Renzoni, EA and Wells, AU and Denton, CP and Laurent, GJ and Abraham, DJ and McAnulty, RJ},
doi = {10.1042/CS20150697},
journal = {Clinical Science},
pages = {575--586},
title = {Epigenetic regulation of cyclooxygenase-2 by methylation of c8orf4 in pulmonary fibrosis},
url = {http://dx.doi.org/10.1042/CS20150697},
volume = {130},
year = {2016}
}

RIS format (EndNote, RefMan)

TY  - JOUR
AB - 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.
AU - Evans,IC
AU - Barnes,JL
AU - Garner,IM
AU - Pearce,DR
AU - Maher,TM
AU - Shiwen,X
AU - Renzoni,EA
AU - Wells,AU
AU - Denton,CP
AU - Laurent,GJ
AU - Abraham,DJ
AU - McAnulty,RJ
DO - 10.1042/CS20150697
EP - 586
PY - 2016///
SN - 1470-8736
SP - 575
TI - Epigenetic regulation of cyclooxygenase-2 by methylation of c8orf4 in pulmonary fibrosis
T2 - Clinical Science
UR - http://dx.doi.org/10.1042/CS20150697
UR - http://hdl.handle.net/10044/1/32679
VL - 130
ER -