Myocardin-related transcription factor A (MRTF-A) plays an essential role in hepatic stellate cell activation by epigenetically modulating TGF-β signaling. (February 2016)

• Record Type: Journal Article
• Authors: Tian, Wenfang; Fan, Zhiwen; Li, Jianfei; Hao, Chenzhi; Li, Min; Xu, Huihui; Wu, Xiaoyan; Zhou, Bisheng; Zhang, Liping; Fang, Mingming; Xu, Yong
• Is Part Of: International journal of biochemistry & cell biology. Volume 71(2016:Feb.)
• Page Start: 35
• Page End: 43
• Publication Date: 2016-02
• Subjects: Liver fibrosis -- MRTF-A -- Hepatic stellate cell -- TGF-β -- Epigenetics -- Histone methylation; Biochemistry -- Periodicals; Cytology -- Periodicals; Biochemistry -- Periodicals; Cell Biology -- Periodicals; Biochimie -- Périodiques; Cytologie -- Périodiques; Biochimie; Cytologie; Biochemistry; Cytology; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); Periodicals; 572.05
• DOI: 10.1016/j.biocel.2015.12.005
• Languages: English
• ISSNs: 1357-2725

Abstract

Highlights: TAA-induced liver injury and fibrosis are attenuated in MRTF-A deficient mice. MRTF-A mediates TGF-β induced pro-fibrogenic transcription in HSCs. MRTF-A recruits a histone H3K4 methyltransferase complex to pro-fibrogenic promoters. COMPASS proteins are essential for pro-fibrogenic transcription in HSCs. Abstract: 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-β, 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-β treatment. Over-expression of ASH2, WDR5, or SET1 enhanced the transactivation of pro-fibrogenic gene promoters by TGF-β in an MRTF-A-dependent manner. In conclusion, MRTF-A regulates liver fibrosis by epigenetically tuning the TGF-β signaling pathway in HSCs.