Premium
Long noncoding RNA MEG3 induces cholestatic liver injury by interaction with PTBP1 to facilitate shp mRNA decay
Author(s) -
Zhang Li,
Yang Zhihong,
Trottier Jocelyn,
Barbier Olivier,
Wang Li
Publication year - 2017
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28882
Subject(s) - meg3 , biology , small heterodimer partner , long non coding rna , rna , microbiology and biotechnology , transcription factor , gene , biochemistry , nuclear receptor
Bile acids (BAs) play critical physiological functions in cholesterol homeostasis, and deregulation of BA metabolism causes cholestatic liver injury. The long noncoding RNA maternally expressed gene 3 (MEG3) was recently shown as a potential tumor suppressor; however, its basic hepatic function remains elusive. Using RNA pull‐down with biotin‐labeled sense or anti‐sense MEG 3 RNA followed by mass spectrometry, we identified RNA‐binding protein polypyrimidine tract‐binding protein 1 (PTBP1) as a MEG3 interacting protein and validated their interaction by RNA immunoprecipitation (RIP). Bioinformatics analysis revealed putative binding sites for PTBP1 within the coding region (CDS) of small heterodimer partner (SHP), a key repressor of BA biosynthesis. Forced expression of MEG3 in hepatocellular carcinoma cells guided and facilitated PTBP1 binding to the Shp CDS, resulting in Shp mRNA decay. Transient overexpression of MEG3 RNA in vivo in mouse liver caused rapid Shp mRNA degradation and cholestatic liver injury, which was accompanied by the disruption of BA homeostasis, elevation of liver enzymes, as well as dysregulation of BA synthetic enzymes and metabolic genes. Interestingly, RNA sequencing coupled with quantitative PCR (qPCR) revealed a drastic induction of MEG3 RNA in Shp −/− liver. SHP inhibited MEG3 gene transcription by repressing cAMP response element‐binding protein (CREB) transactivation of the MEG3 promoter. In addition, the expression of MEG3 and PTBP1 was activated in human fibrotic and cirrhotic livers. Conclusion : MEG3 causes cholestasis by serving as a guide RNA scaffold to recruit PTBP1 to destabilize Shp mRNA. SHP in turn represses CREB‐mediated activation of MEG3 expression in a feedback‐regulatory fashion. (H epatology 2017;65:604‐615).