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Bezerra, J. A.1; Zhang, D.1; Sabla, G.1; Shivakumar, P.1; Tiao, G.1; Sokol, R. J.2; Mack, C.2; Shneider, B. L.3; Aronow, B.4

Journal of Pediatric Gastroenterology and Nutrition: June 2004 - Volume 39 - Issue - p S9
ABSTRACTS: Oral Presentation Abstracts

1 Pediatric Gastroenterology, Hepatology, and Nutrtion, Cincinnati Children’s Hospital Medical Center, Cincinnati, 2 Pediatric Liver Center, The Children’s Hospital, Denver, 3 Pediatric Hepatology, Mount Sinai Medical Center, New York, 4 Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, United States

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Introduction: The molecular basis for the embryonic and perinatal clinical forms of biliary atresia is largely undefined. In this study, we aimed to: 1) determine if the clinical forms can be differentiated at the transcriptional level, and 2) search for molecular mechanisms underlying phenotypic differences.

Methods: To this end, we generated biotinylated cRNA probes from livers of age-matched infants with the embryonic (N=5) and perinatal (N=6) forms of biliary atresia at the time of diagnosis, and hybridized them against the Affymetrix human HG-U133 A and B microarrays containing 44760 gene products.

Results: Subjects were 1–3 months of age, and had similar degrees of hepatocellular injury (as defined by similar levels of serum alanine aminotransferase) and synthetic function (serum albumin and prothrombin time). Data filtering and two-way cluster analysis of the gene expression platform identified 230 genes with an expression profile that is highly distinctive of the clinical phenotypes. Levels of expression of most laterality genes did not change significantly between the groups, neither did the expression of genes encoding Th1 and Th2 cytokines. Functionally, 35% of the profile represented overexpression of regulatory genes, followed by varied metabolic processes. Genes involved in metabolic processes were expressed primarily in livers of infants with the perinatal form, and are involved in oxidation, reduction, hosphorylation, and ubiquination. In contrast, the over-expression of regulatory genes segregated primarily with the diagnosis of the embryonic form, and regulated primarily RNA processing and transcription. Among these regulatory genes, we found a unique pattern of expression of genes involved in chromatin integrity/function (Smarca-1, Rybp, and Hdac3) and the uniform overexpression of five imprinted genes (Igf2, Peg3, Peg10, Meg3, and IPW), implying a failure to downregulate embryonic gene programs.

Conclusion: Embryonic and perinatal forms of biliary atresia are distinguished by gene expression profiling. The coordinate expression of regulators of chromatin structure/function and of imprinted genes suggests a potential pathogenic mechanism in which epigenetic factors modulate phenotypic differences in biliary atresia.

© 2004 Lippincott Williams & Wilkins, Inc.