ABSTRACT: Biliary atresia (BA) is a pediatric liver disease of unknown underlying etiology, in which fibroinflammatory destruction of the extrahepatic biliary system leads to obstructive cholestasis. MicroRNAs are a class of short (18–23 nucleotide), noncoding RNA molecules, which act as negative regulators of target mRNA stability and translation. The importance of these molecules in normal and diseased liver has been demonstrated, but their potential role in the pathogenesis of BA has not been addressed. We have profiled changes in liver microRNA levels in an established mouse model of the disease, identified significantly altered transcripts, and defined the spatial expression patterns of selected microRNAs. Two of these, miR-29a/29b1, are upregulated in experimental BA. Using antisense oligonucleotide-mediated inhibition in mice, we have delineated the full set of hepatic genes regulated by miR-29 and identified 2 mRNA targets of potential pathological relevance in experimental BA, Igf1 and Il1RAP. We have used reporter assays to confirm that Igf1 and Il1RAP are direct targets of miR-29.
Department of Pediatrics, University of Pennsylvania School of Medicine, Children's Hospital of Philadelphia Research Institute, ARC 902G, 3615 Civic Center Blvd, Philadelphia, PA.
Address correspondence and reprint requests to Joshua R. Friedman, Department of Pediatrics, University of Pennsylvania School of Medicine, Children's Hospital of Philadelphia Research Institute, ARC 902G, 3615 Civic Center Blvd, Philadelphia, PA 19104-4318 (e-mail: firstname.lastname@example.org).
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Received 3 November, 2011
Accepted 28 November, 2011
The present study received support from grant NIH R01DK079881 (J.R.F.), the University of Pennsylvania School of Medicine Center for Digestive and Liver Diseases (NIH 5P30DK050306), the American Liver Foundation, and the Fred and Suzanne Biesecker Pediatric Liver Center.
The authors report no conflicts of interest.