RGD Reference Report - A central role for G9a and EZH2 in the epigenetic silencing of cyclooxygenase-2 in idiopathic pulmonary fibrosis. - Rat Genome Database

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

Authors: Coward, WR  Feghali-Bostwick, CA  Jenkins, G  Knox, AJ  Pang, L 
Citation: Coward WR, etal., FASEB J. 2014 Jul;28(7):3183-96. doi: 10.1096/fj.13-241760. Epub 2014 Mar 20.
RGD ID: 9589169
Pubmed: PMID:24652950   (View Abstract at PubMed)
PMCID: PMC4062820   (View Article at PubMed Central)
DOI: DOI:10.1096/fj.13-241760   (Journal Full-text)

Selective silencing of the cyclooxygenase-2 (COX-2) gene with the loss of the antifibrotic mediator prostaglandin E2 contributes to the fibrotic process in idiopathic pulmonary fibrosis (IPF). This study explored the role of G9a- and enhancer of zeste homolog 2 (EZH2)-mediated methylation of histone H3 lysine 9 (H3K9me3) and histone H3 lysine 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 methyl CpG binding protein 2 (MeCP2), at the COX-2 promoter in lung fibroblasts from patients with IPF (F-IPFs) compared with fibroblasts from nonfibrotic lungs. HP1, EZH2, and MeCP2 in turn were associated with additional repressive chromatin modifiers in F-IPFs. G9a and EZH2 inhibitors and small interfering RNAs and the Dnmt1 inhibitor markedly reduced H3K9me3 (49-79%), H3K27me3 (44-81%), and DNA methylation (61-97%) at the COX-2 promoter. These reductions were correlated with increased histone H3 and H4 acetylation, resulting in COX-2 mRNA and protein reexpression in F-IPFs. 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.-Coward, W. R., Feghali-Bostwick, C. A., Jenkins, G., Knox, A. J., Pang, L. A central role for G9a and EZH2 in the epigenetic silencing of cyclooxygenase-2 in idiopathic pulmonary fibrosis.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
idiopathic pulmonary fibrosis  IDA 9589169 RGD 
idiopathic pulmonary fibrosis  ISOEHMT2 (Homo sapiens)9589169; 9589169 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ehmt2  (euchromatic histone lysine methyltransferase 2)

Genes (Mus musculus)
Ehmt2  (euchromatic histone lysine N-methyltransferase 2)

Genes (Homo sapiens)
EHMT2  (euchromatic histone lysine methyltransferase 2)


Additional Information