Analysis of the biliary transcriptome in experimental biliary atresia.
OBJECTIVE
Discovery of the pathogenic mechanisms of biliary atresia has been limited by the inability to study extrahepatic biliary tissues from patients at early phases of disease. Here, we used a rotavirus-induced model of biliary atresia to investigate the entire biliary transcriptome for molecular networks activated at the onset and different phases of progression to duct obstruction.


METHODS
We injected Balb/c mice with saline or rotavirus intraperitoneally within 24 hours of birth, microdissected the gallbladder and extrahepatic bile ducts en bloc 3, 7, and 14 days later, generated biotinylated RNA pools, and hybridized them against microarrays containing 45,101 gene products.


RESULTS
Data filtering, cluster analysis, and functional assignment of the gene expression platform revealed 2 unique patterns of expression. The first was an overarching expression of genes regulating immunity, enzymes, and structural proteins at all phases of atresia. Within this pattern, the sequential expression of the interferon inducers Irf7 and Irf9 at the onset of injury, and interferon-gamma and interferon-gamma-activated genes (Stat1, Igtp, Cxcl9, Cxcl10) at the time of duct obstruction, pointed to a prominent proinflammatory circuit. The second was the time-restricted expression of genes regulating biological networks previously unrecognized in biliary atresia, such as the complement components C3ar-1 and C1q-alpha/beta.


CONCLUSIONS
The coordinate expression of functionally related genes in the biliary transcriptome underscores a predominant proinflammatory footprint and provides a basis for identification of gene groups that may play regulatory roles in the pathogenesis of duct injury and obstruction in experimental biliary atresia.
Carvalho
Elisa
E
Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati, Ohio 45229, USA.
Liu
Cong
C
Shivakumar
Pranavkumar
P
Sabla
Gregg
G
Aronow
Bruce
B
Bezerra
Jorge A
JA
D000818:Animals; D001656:Biliary Atresia / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D018392:Genomic Imprinting; D051379:Mice; D008807:Mice, Inbred BALB C; D012680:Sensitivity and Specificity
D018797:Cell Cycle Proteins