MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis.
MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis.
复制标题
DOI：
10.1053/j.gastro.2009.10.002
复制
发表时间：
2010-02
期刊：
影响因子：
29.4
通讯作者：
Mann DA
中科院分区：
文献类型：
--
作者：
Mann J;Chu DC;Maxwell A;Oakley F;Zhu NL;Tsukamoto H;Mann DA
肌成纤维细胞转分化产生肝肌成纤维细胞，从而促进肝纤维化的形成。过氧化物酶体增殖物激活受体γ是这一过程的负调控因子。我们研究了PPARγ和肌成纤维细胞转分化的表观遗传调控。染色质免疫沉淀分析(CHIP)评估了甲基CpG结合蛋白2(MeCP2)与PPARγ的结合以及使该基因沉默的染色质修饰。在CCl4肝纤维化模型中使用MeCP2-/y小鼠和表观遗传调节蛋白EZH2的抑制剂(DZNep)。取小鼠肝组织进行组织学分析，采用定量聚合酶链式反应(QPCR)检测肝纤维化指标。逆转录-聚合酶链式反应检测到microRNA miR132及其靶基因MeCP2的延长转录本的表达变化。将miR132基因导入肌成纤维细胞，用定量聚合酶链式反应和免疫印迹法检测pPARγ和mecp2的表达。肝星状细胞的肌成纤维细胞转分化是由MeCP2、EZH2和miR132在一个继发通路中的组合控制的。该通路通过下调miR132激活，释放MeCP2上的翻译阻断。MeCP2被招募到PPARγ的5‘端，在那里它促进H3K9的甲基化，并招募转录抑制因子Hp1α。在PPARγ的3‘外显子中，MeCP2还能刺激EZH2的表达和H3K27的甲基化，形成抑制性染色质结构。MeCP2或EZH2的遗传和药物干扰降低了肌成纤维细胞的纤维化特征，并减弱了纤维化形成。肝纤维化由表观遗传的继发通路调节，包括MeCP2、EZH2和miR132。干扰这一途径的试剂可能被开发来减少慢性肝病的纤维化形成。
Myofibroblast transdifferentiation generates hepatic myofibroblasts, which promote liver fibrogenesis. The peroxisome proliferator-activated receptor (PPAR)γ is a negative regulator of this process. We investigated epigenetic regulation of PPARγ and myofibroblast transdifferentiation. Chromatin immunoprecipitation assays (ChIP) assessed binding of methyl-CpG binding protein 2 (MeCP2) to PPARγ and chromatin modifications that silence this gene. MeCP2-/y mice and an inhibitor (DZNep) of the epigenetic regulatory protein EZH2 were used in the CCl4 model of liver fibrosis. Liver tissues from mice were assessed by histological analysis; markers of fibrosis were measured by quantitative PCR (qPCR). Reverse-transcription PCR detected changes in expression of the microRNA miR132 and its target, elongated transcripts of MeCP2. Myofibroblasts were transfected with miR132; PPARγ and MeCP2 expression were analyzed by qPCR or immunoblotting. Myofibroblast transdifferentiation of hepatic stellate cells is controlled by a combination of MeCP2, EZH2, and miR132 in a relay pathway. The pathway is activated by downregulation of miR132, releasing the translational block on MeCP2. MeCP2 is recruited to the 5′ end of PPARγ, where it promotes methylation by H3K9 and recruits the transcription repressor HP1α. MeCP2 also stimulates expression of EZH2 and methylation of H3K27 to form a repressive chromatin structure in the 3′ exons of PPARγ. Genetic and pharmacological disruptions of MeCP2 or EZH2 reduced the fibrogenic characteristics of myofibroblasts and attenuated fibrogenesis. Liver fibrosis is regulated by an epigenetic relay pathway that includes MeCP2, EZH2, and miR132. Reagents that interfere with this pathway might be developed to reduce fibrogenesis in chronic liver disease.
登录
查看更多内容
影响因子：
64.5
作者：
Goldberg, Aaron D.;Allis, C. David;Bernstein, Emily
通讯作者：
Bernstein, Emily
影响因子：
5.1
作者：
Weber, Susanne;Gressner, Olav A.;Lammert, Frank
通讯作者：
Lammert, Frank
影响因子：
4.8
作者：
O'Neill, LP;Turner, BM
通讯作者：
Turner, BM
影响因子：
14.9
作者：
Fuks, F;Hurd, PJ;Kouzarides, T
通讯作者：
Kouzarides, T
影响因子：
2.9
作者：
Desmoulière, A;Chaponnier, C;Gabbiani, G
通讯作者：
Gabbiani, G