A central role for G9a and EZH2 in the epigenetic silencing of cyclooxygenase-2 in idiopathic pulmonary fibrosis.
A central role for G9a and EZH2 in the epigenetic silencing of cyclooxygenase-2 in idiopathic pulmonary fibrosis.
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DOI：
10.1096/fj.13-241760
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发表时间：
2014-07
期刊：
影响因子：
--
通讯作者：
Pang L
中科院分区：
文献类型：
--
作者：
Coward WR;Feghali-Bostwick CA;Jenkins G;Knox AJ;Pang L
环氧化酶-2（考克斯-2）基因的选择性沉默伴随抗纤维化介质前列腺素E2的丢失导致特发性肺纤维化（IPF）的纤维化过程。本研究探讨了G9 a和zeste同源物2增强子（EZH 2）介导的组蛋白H3赖氨酸9（H3 K9 me 3）和组蛋白H3赖氨酸27（H3 K27 me 3）甲基化在IPF中考克斯-2沉默中的作用。染色质免疫沉淀（ChIP）和re-ChIP测定显示H3 K9 me 3、H3 K27 me 3和DNA甲基化以及它们各自的修饰酶G9 a、EZH 2和DNA甲基转移酶（Dnmts）和各自的结合蛋白异染色质蛋白1（HP 1）、多梳蛋白复合物1（PRC 1）和甲基CpG结合蛋白2（MeCP 2）显著增加，与来自非纤维化肺的成纤维细胞相比，来自IPF患者的肺成纤维细胞（F-IPF）中的考克斯-2启动子。HP 1、EZH 2和MeCP 2依次与F-IPF中的其他抑制性染色质修饰剂相关。G9 a和EZH 2抑制剂和小干扰RNA以及Dnmt 1抑制剂显著降低了考克斯-2启动子处的H3 K9 me 3（49−79%）、H3 K27 me 3（44−81%）和DNA甲基化（61−97%）。这些减少与组蛋白H3和H4乙酰化增加相关，导致F-IPF中考克斯-2 mRNA和蛋白的重新表达。我们的研究结果支持G9 a和EZH 2介导的组蛋白超甲基化的核心作用，以及组蛋白超甲基化和DNA甲基化在IPF的考克斯-2表观遗传沉默中的双向、相互增强和相互依赖的串扰模型。科沃德，W。R.，费加利-博斯特威克角一、詹金斯，G.，诺克斯，A。J.，庞湖，澳-地G9 a和EZH 2在特发性肺纤维化中环氧合酶-2的表观遗传沉默中的核心作用
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.
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影响因子：
4.2
作者：
Kondo, Yutaka;Shen, Lanlan;Sekido, Yoshitaka
通讯作者：
Sekido, Yoshitaka
影响因子：
6
作者：
Pilewski, JM;Liu, LX;Feghali-Bostwick, CA
通讯作者：
Feghali-Bostwick, CA
影响因子：
5.3
作者：
Coward, William R.;Watts, Keira;Pang, Linhua
通讯作者：
Pang, Linhua
影响因子：
16
作者：
Kubicek, Stefan;O'Sullivan, Roderick J.;Jenuwein, Thomas
通讯作者：
Jenuwein, Thomas
DOI：
10.1164/ajrccm/144.5.1080
发表时间：
1991-11-01
期刊：
AMERICAN REVIEW OF RESPIRATORY DISEASE
影响因子：
--
作者：
BOROK, Z;GILLISSEN, A;CRYSTAL, RG
通讯作者：
CRYSTAL, RG