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Myocardin related transcription factor A programs epigenetic activation of hepatic stellate cells

Wenfang Tian1, Chenzhi Hao1, Zhiwen Fan1

  • 1State Key Laboratory of Reproductive Medicine, Department of Pathophysiology, Key Laboratory of Cardiovascular Disease, Nanjing Medical University, Nanjing, Jiangsu, China.

Journal of Hepatology
|August 12, 2014
PubMed

Insights

Myocardin related transcription factor A (MRTF-A) drives hepatic stellate cell activation and liver fibrosis by recruiting COMPASS to fibrogenic gene promoters. Blocking MRTF-A or COMPASS inhibits fibrosis, offering new therapeutic targets for liver disease.

Area of Science:

  • Epigenetics
  • Liver Pathophysiology
  • Cell Biology

Background:

  • Hepatic stellate cell (HSC) activation is central to liver injury and cirrhosis.
  • The role of epigenetic machinery in HSC activation remains incompletely understood.
  • Myocardin related transcription factor A (MRTF-A) is investigated for its role in HSC activation.

Purpose of the Study:

  • To elucidate the function of MRTF-A in hepatic stellate cell activation.
  • To investigate the epigenetic mechanisms underlying liver fibrosis.
  • To identify potential therapeutic targets for liver disease.

Main Methods:

  • Induction of liver fibrosis in wild type and MRTF-A deficient mice.
  • Quantitative analysis of gene and protein expression (real-time PCR, Western blotting, immunohistochemistry).
  • Chromatin immunoprecipitation (ChIP) assays to assess protein-DNA binding and histone modifications.
  • Lentiviral-mediated knockdown using siRNA and shRNA.

Main Results:

  • MRTF-A deficient mice showed resistance to liver fibrosis.
  • Suppression of activated HSC signature genes in the absence of MRTF-A.
  • MRTF-A deficiency erased key histone modifications (H3K4 di- and tri-methylation) at fibrogenic gene promoters.
  • MRTF-A recruits the COMPASS complex to activate fibrogenic genes; COMPASS component silencing blocked fibrosis.
  • Oestradiol inhibited HSC activation by reducing COMPASS expression and binding.

Conclusions:

  • A novel mechanism linking MRTF-A-dependent histone H3K4 methylation to HSC activation is identified.
  • MRTF-A and the COMPASS complex are critical regulators of fibrogenic gene transcription in HSCs.
  • These findings highlight potential therapeutic strategies for liver fibrosis targeting the MRTF-A/COMPASS pathway.
Abstract

Keywords:
EpigeneticsHepatic stellate cellLiver fibrosisTranscriptional regulation

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