Integrative genomics identifies candidate microRNAs for pathogenesis of experimental biliary atresia

Biliary atresia is a fibroinflammatory obstruction of extrahepatic bile duct that leads to end-stage liver disease in children. Despite advances in understanding the pathogenesis of biliary atresia, very little is known about the role of microRNAs (miRNAs) in onset and progression of the disease. In...

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Bibliographic Details
Published in:BMC systems biology 2013-10, Vol.7 (1), p.104-104, Article 104
Main Authors: Bessho, Kazuhiko, Shanmukhappa, Kumar, Sheridan, Rachel, Shivakumar, Pranavkumar, Mourya, Reena, Walters, Stephanie, Kaimal, Vivek, Dilbone, Eric, Jegga, Anil G, Bezerra, Jorge A
Format: Article
Language:English
Subjects:
Analysis
Animals
Bile Ducts - metabolism
Biliary atresia
Biliary Atresia - genetics
Children
Development and progression
Diseases
Experiments
Gallbladder
Gallbladder - metabolism
Gene expression
Gene Expression Profiling
Genes
Genetic aspects
Genetic research
Genomics
Hybridization
Liver
Liver diseases
Medical research
Medicine, Experimental
Mice
MicroRNA
MicroRNAs
MicroRNAs - genetics
Pathogenesis
Rodents
Studies
Time Factors
Viruses
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Summary:Biliary atresia is a fibroinflammatory obstruction of extrahepatic bile duct that leads to end-stage liver disease in children. Despite advances in understanding the pathogenesis of biliary atresia, very little is known about the role of microRNAs (miRNAs) in onset and progression of the disease. In this study, we aimed to investigate the entire biliary transcriptome to identify miRNAs with potential role in the pathogenesis of bile duct obstruction. By profiling the expression levels of miRNA in extrahepatic bile ducts and gallbladder (EHBDs) from a murine model of biliary atresia, we identified 14 miRNAs whose expression was suppressed at the times of duct obstruction and atresia (≥2 fold suppression, P < 0.05, FDR 5%). Next, we obtained 2,216 putative target genes of the 14 miRNAs using in silico target prediction algorithms. By integrating this result with a genome-wide gene expression analysis of the same tissue (≥2 fold increase, P < 0.05, FDR 5%), we identified 26 potential target genes with coordinate expression by the 14 miRNAs. Functional analysis of these target genes revealed a significant relevance of miR-30b/c, -133a/b, -195, -200a, -320 and -365 based on increases in expression of at least 3 target genes in the same tissue and 1st-to-3rd tier links with genes and gene-groups regulating organogenesis and immune response. These miRNAs showed higher expression in EHBDs above livers, a unique expression in cholangiocytes and the subepithelial compartment, and were downregulated in a cholangiocyte cell line after RRV infection. Integrative genomics reveals functional relevance of miR-30b/c, -133a/b, -195, -200a, -320 and -365. The coordinate expression of miRNAs and target genes in a temporal-spatial fashion suggests a regulatory role of these miRNAs in pathogenesis of experimental biliary atresia.
ISSN:1752-0509
1752-0509
DOI:10.1186/1752-0509-7-104