A central role for G9a and EZH2 in the epigenetic silencing of cyclooxygenase-2 in idiopathic pulmonary fibrosis
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) i...
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| Format: | Article |
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Federation of American Society of Experimental Biology
2014
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| Online Access: | https://eprints.nottingham.ac.uk/31459/ |
| _version_ | 1848794208425476096 |
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| author | Coward, William R. Feghali-Bostwick, Carol A. Jenkins, Gisli Knox, Alan J. Pang, Linhua |
| author_facet | Coward, William R. Feghali-Bostwick, Carol A. Jenkins, Gisli Knox, Alan J. Pang, Linhua |
| author_sort | Coward, William R. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:12:32Z |
| format | Article |
| id | nottingham-31459 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:12:32Z |
| publishDate | 2014 |
| publisher | Federation of American Society of Experimental Biology |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-314592020-05-04T16:44:30Z https://eprints.nottingham.ac.uk/31459/ A central role for G9a and EZH2 in the epigenetic silencing of cyclooxygenase-2 in idiopathic pulmonary fibrosis Coward, William R. Feghali-Bostwick, Carol A. Jenkins, Gisli Knox, Alan J. Pang, Linhua 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. Federation of American Society of Experimental Biology 2014-03-20 Article PeerReviewed Coward, William R., Feghali-Bostwick, Carol A., Jenkins, Gisli, 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 http://www.fasebj.org/content/28/7/3183.full.pdf+html doi:10.1096/fj.13-241760 doi:10.1096/fj.13-241760 |
| spellingShingle | Coward, William R. Feghali-Bostwick, Carol A. Jenkins, Gisli Knox, Alan J. Pang, Linhua A central role for G9a and EZH2 in the epigenetic silencing of cyclooxygenase-2 in idiopathic pulmonary fibrosis |
| title | A central role for G9a and EZH2 in the epigenetic silencing of cyclooxygenase-2 in idiopathic pulmonary fibrosis |
| title_full | A central role for G9a and EZH2 in the epigenetic silencing of cyclooxygenase-2 in idiopathic pulmonary fibrosis |
| title_fullStr | A central role for G9a and EZH2 in the epigenetic silencing of cyclooxygenase-2 in idiopathic pulmonary fibrosis |
| title_full_unstemmed | A central role for G9a and EZH2 in the epigenetic silencing of cyclooxygenase-2 in idiopathic pulmonary fibrosis |
| title_short | A central role for G9a and EZH2 in the epigenetic silencing of cyclooxygenase-2 in idiopathic pulmonary fibrosis |
| title_sort | central role for g9a and ezh2 in the epigenetic silencing of cyclooxygenase-2 in idiopathic pulmonary fibrosis |
| url | https://eprints.nottingham.ac.uk/31459/ https://eprints.nottingham.ac.uk/31459/ https://eprints.nottingham.ac.uk/31459/ |