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Long noncoding RNA MEG3 induces cholestatic liver injury by interaction with PTBP1 to facilitate shp mRNA decay

Li Zhang1, Zhihong Yang1,2, Jocelyn Trottier3

  • 1Department of Physiology and Neurobiology and Institute for Systems Genomics, University of Connecticut, Storrs, CT.

Hepatology (Baltimore, Md.)
|October 23, 2016
PubMed

Insights

The long noncoding RNA MEG3 recruits PTBP1 to degrade SHP mRNA, causing cholestatic liver injury. This highlights a novel regulatory pathway in bile acid metabolism and liver disease.

Area of Science:

  • Molecular Biology
  • Hepatology
  • RNA Biology

Background:

  • Bile acids (BAs) are crucial for cholesterol homeostasis; their metabolic dysregulation leads to cholestatic liver injury.
  • The function of the long noncoding RNA maternally expressed gene 3 (MEG3) in liver physiology is largely unknown.
  • MEG3 has been identified as a potential tumor suppressor, but its role in normal hepatic function requires elucidation.

Purpose of the Study:

  • To investigate the role of MEG3 in hepatic bile acid metabolism and its potential contribution to cholestatic liver injury.
  • To identify proteins interacting with MEG3 in the liver.
  • To elucidate the molecular mechanism by which MEG3 influences bile acid homeostasis.

Main Methods:

  • RNA pull-down assay followed by mass spectrometry to identify MEG3-interacting proteins.
  • RNA immunoprecipitation (RIP) to validate protein-RNA interactions.
  • In vitro (hepatocellular carcinoma cells) and in vivo (mouse liver) experiments to assess the effects of MEG3 overexpression on SHP mRNA stability and liver injury.
  • RNA sequencing and quantitative PCR (qPCR) to analyze gene expression changes.
  • Bioinformatics analysis to predict PTBP1 binding sites.

Main Results:

  • Polypyrimidine tract-binding protein 1 (PTBP1) was identified as a MEG3-interacting protein.
  • MEG3 facilitates PTBP1 binding to the coding region of small heterodimer partner (SHP) mRNA, leading to Shp mRNA decay.
  • Overexpression of MEG3 in vivo induced Shp mRNA degradation, causing cholestatic liver injury, disrupted bile acid homeostasis, elevated liver enzymes, and altered expression of BA metabolism genes.
  • MEG3 RNA was significantly induced in Shp knockout livers, and SHP repressed MEG3 transcription via CREB.
  • MEG3 and PTBP1 expression were elevated in human fibrotic and cirrhotic livers.

Conclusions:

  • MEG3 induces cholestasis by acting as a scaffold for PTBP1, promoting Shp mRNA destabilization.
  • SHP negatively regulates MEG3 expression through a feedback loop involving CREB.
  • This MEG3-PTBP1-SHP axis represents a novel mechanism contributing to cholestatic liver injury and may be relevant in human liver fibrosis and cirrhosis.

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