A central role for G9a and EZH2 in the epigenetic silencing of cyclooxygenase-2 in idiopathic pulmonary fibrosis

Coward, William R. and Feghali-Bostwick, Carol A. and Jenkins, Gisli and Knox, Alan J. and Pang, Linhua (2014) A central role for G9a and EZH2 in the epigenetic silencing of cyclooxygenase-2 in idiopathic pulmonary fibrosis. FASEB Journal, 28 (7). pp. 3183-3196. ISSN 0892-6638

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Abstract

Selective silencing of the cyclooxygenase-2 (COX-2) gene with the loss of the antifibrotic mediator PGE2 contributes to the fibrotic process in idiopathic pulmonary fibrosis (IPF). This study explored the role of G9a- and EZH2-mediated methylation of histone H3 lysine 9 (H3K9me3) and 27 (H3K27me3) in COX-2 silencing in IPF. Chromatin immunoprecipitation (ChIP) and Re-ChIP assays demonstrated marked increases in H3K9me3, H3K27me3 and DNA methylation, together with their respective modifying enzymes G9a, EZH2 and DNA methyltransferases (Dnmts) and respective binding proteins heterochromatin protein 1 (HP1), polycomb protein complex 1 (PRC1) and MeCP2, at the COX-2 promoter in lung fibroblasts from IPF patients (F-IPF) compared with fibroblasts from non-fibrotic lungs (F-NL). HP1, EZH2 and MeCP2 in turn were associated with additional repressive chromatin modifiers in F-IPF. G9a and EZH2 inhibitors and siRNAs and Dnmt1 inhibitor markedly reduced H3K9me3 (49-79%), H3K27me3 (44-81%) and DNA methylation (61-97%) at the COX-2 promoter. This was correlated with increased histone H3 and H4 acetylation, resulting in COX-2 mRNA and protein re-expression in F-IPF. Our results support a central role for G9a- and EZH2-mediated histone hypermethylation and a model of bidirectional, mutually reinforcing and interdependent crosstalk between histone hypermethylation and DNA methylation in COX-2 epigenetic silencing in IPF.

Item Type: Article
Schools/Departments: University of Nottingham UK Campus > Faculty of Medicine and Health Sciences > School of Medicine > Division of Respiratory Medicine
Identification Number: https://doi.org/10.1096/fj.13-241760
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Depositing User: Pang, Linhua
Date Deposited: 01 Feb 2016 13:10
Last Modified: 14 Sep 2016 14:48
URI: http://eprints.nottingham.ac.uk/id/eprint/31459

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