Han Xinrui, Hao Chenzhi, Li Luyang, Li Jianfei, Fang Mingming, Zheng Yuanlin, Lu Jun, Li Ping, Xu Yong
Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China.
Department of Pathophysiology, Key Laboratory of Cardiovascular Disease and Molecular Intervention, Nanjing Medical University, Nanjing, China.
Oncotarget. 2017 Jul 18;8(29):47586-47594. doi: 10.18632/oncotarget.17739.
Activation of hepatic stellate cells (HSCs) is a hallmark event during liver fibrogenesis. We have previously shown that the transcriptional modulator MRTF-A contributes to liver fibrosis by programming epigenetic activation of HSCs. In the present study we investigated the mechanism whereby MRTF-A expression is regulated in this process. We report here that MRTF-A protein levels, but not mRNA levels, were up-regulated in vivo in the livers of mice induced to develop hepatic fibrosis. Pro-fibrogenic stimuli (TGF-β and PDGF-BB) also activated MRTF-A expression post-transcriptionally in vitro in cultured HSCs. miR-206 bound to the 3'-UTR of MRTF-A presumably to inhibit translation. miR-206 levels were down-regulated in response to pro-fibrogenic stimuli in vivo and in vitro allowing MRTF-A proteins to accumulate. Mechanistically, histone deacetylase 4 (HDAC4) was induced by pro-fibrogenic stimuli and recruited to the miR-206 promoter to repress miR-206 transcription. HDAC4 stimulated MRTF-A expression and drove fibrogenesis in HSCs in a miR-206 dependent manner. Therefore, our data reveal an HDAC4-miR-206-MRTF-A axis that can play a potentially important role in HSC activation and liver fibrosis.
肝星状细胞（HSCs）的激活是肝纤维化过程中的一个标志性事件。我们之前已经表明，转录调节因子MRTF-A通过对HSCs进行表观遗传激活来促进肝纤维化。在本研究中，我们探究了在此过程中MRTF-A表达的调控机制。我们在此报告，在诱导发生肝纤维化的小鼠肝脏中，MRTF-A的蛋白水平而非mRNA水平在体内上调。促纤维化刺激因子（TGF-β和PDGF-BB）在体外培养的HSCs中也在转录后激活了MRTF-A的表达。miR-206与MRTF-A的3'-UTR结合，推测是为了抑制翻译。在体内和体外，miR-206的水平因促纤维化刺激而下调，从而使MRTF-A蛋白得以积累。从机制上讲，组蛋白去乙酰化酶4（HDAC4）由促纤维化刺激诱导产生，并被招募到miR-206启动子处，以抑制miR-206的转录。HDAC4以miR-206依赖的方式刺激MRTF-A的表达并驱动HSCs中的纤维化形成。因此，我们的数据揭示了一个HDAC4-miR-206-MRTF-A轴，其可能在HSC激活和肝纤维化中发挥重要作用。
