|ZFIN ID: ZDB-PUB-110221-11|
DNA hypomethylation causes bile duct defects in zebrafish and is a distinguishing feature of infantile biliary atresia
Matthews, R.P., Eauclaire, S.F., Mugnier, M., Lorent, K., Cui, S., Ross, M.M., Zhang, Z., Russo, P., and Pack, M.
|Source:||Hepatology (Baltimore, Md.) 53(3): 905-914 (Journal)|
|Registered Authors:||Lorent, Kristin, Matthews, Randy, Pack, Michael|
|PubMed:||21319190 Full text @ Hepatology|
Matthews, R.P., Eauclaire, S.F., Mugnier, M., Lorent, K., Cui, S., Ross, M.M., Zhang, Z., Russo, P., and Pack, M. (2011) DNA hypomethylation causes bile duct defects in zebrafish and is a distinguishing feature of infantile biliary atresia. Hepatology (Baltimore, Md.). 53(3):905-914.
ABSTRACTInfantile cholestatic disorders arise in the context of progressively developing intrahepatic bile ducts. Biliary atresia (BA), a progressive fibroinflammatory disorder of extra- and intrahepatic bile ducts, is the most common identifiable cause of infantile cholestasis and the leading indication for liver transplantation in children. The etiology of BA is unclear, and although there is some evidence for viral, toxic, and complex genetic causes, the exclusive occurrence of BA during a period of biliary growth and remodeling suggests an importance of developmental factors. Interestingly, interferon-γ (IFN-γ) signaling is activated in patients and in the frequently utilized rhesus rotavirus mouse model of BA, and is thought to play a key mechanistic role. Here we demonstrate intrahepatic biliary defects and up-regulated hepatic expression of IFN-γ pathway genes caused by genetic or pharmacological inhibition of DNA methylation in zebrafish larvae. Biliary defects elicited by inhibition of DNA methylation were reversed by treatment with glucocorticoid, suggesting that the activation of inflammatory pathways was critical. DNA methylation was significantly reduced in bile duct cells from BA patients compared to patients with other infantile cholestatic disorders, thereby establishing a possible etiologic link between decreased DNA methylation, activation of IFN-γ signaling, and biliary defects in patients. Conclusion: Inhibition of DNA methylation leads to biliary defects and activation of IFN-γ-responsive genes, thus sharing features with BA, which we determine to be associated with DNA hypomethylation. We propose epigenetic activation of IFN-γ signaling as a common etiologic mechanism of intrahepatic bile duct defects in BA.