Myocardin-related transcription factor A (MRTF-A) plays an essential role in hepatic stellate cell activation by epigenetically modulating TGF-β signaling

被引：45

作者：

Tian, Wenfang ^{[1
]}

Fan, Zhiwen ^{[1
]}

Li, Jianfei ^{[1
]}

Hao, Chenzhi ^{[1
]}

Li, Min ^{[1
]}

Xu, Huihui ^{[1
]}

Wu, Xiaoyan ^{[1
]}

Zhou, Bisheng ^{[1
]}

Zhang, Liping ^{[3
]}

Fang, Mingming ^{[1
,2
]}

Xu, Yong ^{[1
]}

机构：

[1] Nanjing Med Univ, Dept Pathophysiol, Key Lab Cardiovasc Dis, Nanjing 210029, Jiangsu, Peoples R China

[2] Jiangsu Jiankang Vocat Univ, Dept Nursing, Nanjing, Jiangsu, Peoples R China

[3] Xinjiang Med Uinvers, Dept Biochem, Urumqi, Peoples R China

来源：

INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY | 2016年 / 71卷

基金：

中国国家自然科学基金;

关键词：

Liver fibrosis; MRTF-A; Hepatic stellate cell; TGF-beta; Epigenetics; Histone methylation; PRO-INFLAMMATORY TRANSCRIPTION; BRAHMA-RELATED GENE-1; FIBROSIS; TRANSACTIVATION; COMPASS; PATHWAY; COMPLEX; SMAD3; EXPRESSION; INDUCTION;

D O I：

10.1016/j.biocel.2015.12.005

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Fibrosis following injury is a common adaptive response in the liver, which can lead to irreparable and life-threatening cirrhosis and hepatocellular carcinoma without effectual intervention. The molecular mechanisms underlying fibrogenic response in the liver remains poorly understood. Here we report that mice with deficiency in myocardin-related transcription factor A (MRTF-A) showed resistance to thioacetamide (TAA)-induced liver fibrosis with significantly reduced expression of pro-fibrogenic genes when compared to wild type littermates. Over-expression of MRTF-A enhanced whereas depletion of MRTF-A alleviated pro-fibrogenic transcription induced by TGF-beta, a major pro-fibrogenic factor in hepatic stellate cells (HSCs). Mechanistically, MRTF-A silencing in HSCs impacted the chromatin structure by reducing the deposition of methylated histone H3K4 on the promoters of pro-fibrogenic genes. Further analyses revealed that MRTF-A interacted with and recruited several key epigenetic factors involved in H3K4 methylation, including ASH2, WDR5, and SET1, to the promoters of pro-fibrogenic genes in response to TGF-beta treatment. Over-expression of ASH2, WDR5, or SET1 enhanced the transactivation of pro-fibrogenic gene promoters by TGF-beta in an MRTF-A-dependent manner. In conclusion, MRTF-A regulates liver fibrosis by epigenetically tuning the TGF-beta signaling pathway in HSCs. (C) 2015 Elsevier Ltd. All rights reserved.

引用

页码：35 / 43

页数：9

共 37 条

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