Document Detail


Epigenetic regulation of miR-34a expression in alcoholic liver injury.
MedLine Citation:
PMID:  22841474     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Epigenetic changes are associated with the regulation of transcription of key cell regulatory genes [micro RNAs (miRNAs)] during different types of liver injury. This study evaluated the role of methylation-associated miRNA, miR-34a, in alcoholic liver diseases. We identified that ethanol feeding for 4 weeks significantly up-regulated 0.8% of known miRNA compared with controls, including miR-34a. Treatment of normal human hepatocytes (N-Heps) and cholangiocytes [human intrahepatic biliary epithelial cells (HiBECs)] with ethanol and lipopolysaccharide induced a significant increase of miR-34a expression. Overexpression of miR-34a decreased ethanol-induced apoptosis in both N-Heps and HiBECs. In support of the concept that the 5'-promoter region of miR-34a was noted to be embedded within a CpG island, the expression level of miR-34a was significantly increased after demethylation treatment in N-Heps and HiBECs. By methylation-specific PCR, we confirmed that miR-34a activation is associated with ethanol-linked hypomethylation of the miR-34a promoter. A combination of bioinformatics, dual-luciferase reporter assay, mass spectrometry, and Western blot analysis revealed that caspase-2 and sirtuin 1 are the direct targets of miR-34a. Furthermore, modulation of miR-34a also altered expression of matrix metalloproteases 1 and 2, the mediators involved in hepatic remodeling during alcoholic liver fibrosis. These findings provide the basis for an exciting field in which the epigenomic microRNAs of hepatic cells may be manipulated with potential therapeutic benefits in human alcoholic liver diseases.
Authors:
Fanyin Meng; Shannon S Glaser; Heather Francis; Fuquan Yang; Yuyan Han; Allison Stokes; Dustin Staloch; Jennifer McCarra; Jingang Liu; Julie Venter; Haiying Zhao; Xiuping Liu; Taylor Francis; Scott Swendsen; Chang-Gong Liu; Hidekazu Tsukamoto; Gianfranco Alpini
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-25
Journal Detail:
Title:  The American journal of pathology     Volume:  181     ISSN:  1525-2191     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-08-20     Completed Date:  2012-11-08     Revised Date:  2013-09-03    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  804-17     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Affiliation:
Department of Medicine, Scott & White Digestive Disease Research Center, Texas A&M Health Science Center College of Medicine, Temple, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Base Sequence
Caspase 2 / metabolism
Cell Line
Cell Movement / genetics
Cell Survival / genetics
Cell Transformation, Neoplastic
DNA (Cytosine-5-)-Methyltransferase / metabolism
DNA Methylation / genetics
Disease Models, Animal
Epigenesis, Genetic*
Ethanol
Fatty Liver / genetics,  pathology
Gene Silencing
Humans
Liver / metabolism,  pathology
Liver Diseases, Alcoholic / enzymology,  genetics*,  pathology
Matrix Metalloproteinases / genetics,  metabolism
Mice
Mice, Inbred C57BL
MicroRNAs / genetics*,  metabolism
Molecular Sequence Data
Polymerase Chain Reaction
Sirtuin 1 / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
DK76898/DK/NIDDK NIH HHS; P50AA011999/AA/NIAAA NIH HHS; R01 DK054811/DK/NIDDK NIH HHS; R01 DK076898/DK/NIDDK NIH HHS; R01-DK081442/DK/NIDDK NIH HHS; R01DK054811/DK/NIDDK NIH HHS; U01 AA018663/AA/NIAAA NIH HHS
Chemical
Reg. No./Substance:
0/MIRN34 microRNA, human; 0/MIRN34 microRNA, mouse; 0/MicroRNAs; 64-17-5/Ethanol; EC 2.1.1.37/DNA (Cytosine-5-)-Methyltransferase; EC 2.1.1.37/DNA methyltransferase 3B; EC 3.4.22.-/Caspase 2; EC 3.4.24.-/Matrix Metalloproteinases; EC 3.5.1.-/Sirtuin 1
Comments/Corrections

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