title: Integrative genomics identifies candidate microRNAs for pathogenesis of experimental biliary atresia.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Bessho
authors.forename: Kumar
authors.initials: K
authors.lastname: Shanmukhappa
authors.forename: Rachel
authors.initials: R
authors.lastname: Sheridan
authors.forename: Pranavkumar
authors.initials: P
authors.lastname: Shivakumar
authors.forename: Reena
authors.initials: R
authors.lastname: Mourya
authors.forename: Stephanie
authors.initials: S
authors.lastname: Walters
authors.forename: Vivek
authors.initials: V
authors.lastname: Kaimal
authors.forename: Eric
authors.initials: E
authors.lastname: Dilbone
authors.forename: Anil G
authors.initials: AG
authors.lastname: Jegga
authors.affiliation: Cincinnati Children's Hospital Medical Center and Departments of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA. Jorge.bezerra@cchmc.org.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Bezerra
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000378:metabolism; D001656:Biliary Atresia / Q000235:genetics*; D005704:Gallbladder / Q000378:metabolism; D020869:Gene Expression Profiling; D023281:Genomics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D013997:Time Factors
chemical_list: D035683:MicroRNAs