title: Myocardin related transcription factor A programs epigenetic activation of hepatic stellate cells.
abstract: OBJECTIVE
  Activation of hepatic stellate cells (HSCs) represents a key process in liver injury and, in the absence of intervention, leads to irreversible cirrhosis contributing significantly to the mortality of patients with liver disease. A missing link in the current understanding of HSC activation is the involvement of the epigenetic machinery. We investigated the role of the myocardin related transcription factor A (MRTF-A) in HSC activation.
  
  
  METHODS
  Liver fibrosis was induced in wild type (WT) and MRTF-A deficient (KO) mice by CCl4 injection. Expression of mRNA and protein was measured by real-time PCR, Western blotting, and immunohistochemistry. Protein binding to DNA was assayed by chromatin immunoprecipitation (ChIP). Knockdown of endogenous proteins was mediated by either small interfering RNA (siRNA) or short hairpin RNA (shRNA), carried by lentiviral particles.
  
  
  RESULTS
  KO mice exhibited resistance to CCl4-induced liver fibrosis compared to WT littermates. The expression of activated HSC signature genes was suppressed in the absence of MRTF-A. ChIP assays revealed that MRTF-A deficiency led to the erasure of key histone modifications, associated with transcriptional activation, such as H3K4 di- and tri-methylation, on the promoter regions of fibrogenic genes. Mechanistically, MRTF-A recruited a histone methyltransferase complex (COMPASS) to the promoters of fibrogenic genes to activate transcription. Silencing of individual COMPASS components dampened transactivation of fibrogenic genes in vitro and blocked liver fibrosis in mice. Oestradiol suppressed HSC activation by dampening the expression and binding activity of COMPASS.
  
  
  CONCLUSIONS
  Our data illustrate a novel mechanism that connects MRTF-A dependent histone H3K4 methylation to HSC activation.
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Tian
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Chenzhi
authors.initials: C
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Weng
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Fang
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease, Nanjing Medical University, Nanjing, Jiangsu, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Key Laboratory of Inflammation and Molecular Targets, Medical College, Nantong University, Nantong, Jiangsu, China. Electronic address: shen_aiguo@yahoo.com.
authors.forename: Aiguo
authors.initials: A
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease, Nanjing Medical University, Nanjing, Jiangsu, China. Electronic address: yxu2005@gmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D008106:Liver Cirrhosis, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D000099251:Myocardin
chemical_list: D009687:Nuclear Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D000099251:Myocardin
keywords: Epigenetics; Hepatic stellate cell; Liver fibrosis; Transcriptional regulation