Integrative genomics identifies candidate microRNAs for pathogenesis of experimental biliary atresia
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE41595 | GEO | 2013/10/15
SECONDARY ACCESSION(S): PRJNA177625
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-10-15 | E-GEOD-41595 | biostudies-arrayexpress
Project description:BackgroundBiliary 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.ResultsBy 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.ConclusionsIntegrative 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.
| S-EPMC3819657 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2013-06-01 | E-GEOD-46995 | biostudies-arrayexpress
Project description:Hepatic microRNA was measured by Exiqon array in the mouse RRV model of biliary atresia miRNA expression profiling. For the miRNA microarray experiment, RRV and saline injected animals were euthanized at 3, 8, and 14 days post infection (n=5 per treatment, per time point), and total RNA was purified from liver using the mirVana miRNA Isolation Kit (Ambion) according to the manufacturer's instructions. A pooled common control was assembled from an equal RNA mass from each of the samples, and samples and control were separately dye-labeled, and hybridized to a miRcury v11.0 miRNA microarray (Exiqon) at the University of Pennsylvania School of Medicine Microarray core facility. Sample hybridization intensities were scored relative to the common control, and raw intensity data were normalized and analyzed using the SAM add-in for Microsoft Excel. MiRNAs exhibiting a fold-change of greater than 10% up or down, at a false discovery rate of 5% were chosen for further study.
2011-11-04 | GSE33418 | GEO
Project description:Hepatic microRNA was measured by Exiqon array in the mouse RRV model of biliary atresia miRNA expression profiling. For the miRNA microarray experiment, RRV and saline injected animals were euthanized at 3, 8, and 14 days post infection (n=5 per treatment, per time point), and total RNA was purified from liver using the mirVana miRNA Isolation Kit (Ambion) according to the manufacturer's instructions. A pooled common control was assembled from an equal RNA mass from each of the samples, and samples and control were separately dye-labeled, and hybridized to a miRcury v11.0 miRNA microarray (Exiqon) at the University of Pennsylvania School of Medicine Microarray core facility. Sample hybridization intensities were scored relative to the common control, and raw intensity data were normalized and analyzed using the SAM add-in for Microsoft Excel. MiRNAs exhibiting a fold-change of greater than 10% up or down, at a false discovery rate of 5% were chosen for further study. Three time points (3, 8, 14 days) x 2 conditions x 6 replicates - 1 failed sample = 35 samples
2011-11-04 | E-GEOD-33418 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2013-06-01 | GSE46995 | GEO
Project description:UnlabelledBiliary atresia (BA) is a progressive fibroinflammatory obstruction of extrahepatic bile ducts that presents as neonatal cholestasis. Due to the overlap in clinical, biochemical, and histological features with other causes of cholestasis, the diagnosis requires an intraoperative cholangiogram. Thus, we determined whether diseased livers express a gene expression signature unique to BA. Applying stringent statistical analysis to a genome-wide liver expression platform of 64 infants with BA at the time of diagnosis, 14 age-appropriate subjects with intrahepatic cholestasis as diseased controls and seven normal controls, we identified 15 genes uniquely expressed in BA with an accuracy of 92.3%. Among these genes, IL8 and LAMC2 were sufficient to classify subjects with BA distinctly from diseased controls with an area under the curve of 0.934 (95% confidence interval [CI]: 0.84-1.03), sensitivity of 96.9%, and specificity of 85.7% using their combined first principal component. Direct measurement of interleukin (IL)8 protein in the serum, however, was not different between the two groups. To investigate whether the liver-restricted increase in IL8 was relevant to disease pathogenesis, we inactivated the signaling of IL8 homologs by genetic targeting of the Cxcr2 receptor in a murine model of experimental BA. Disruption of Cxcr2 shortened the duration of cholestasis, decreased the incidence of bile duct obstruction, and improved survival above wild-type neonatal mice.ConclusionThe hepatic expression of IL8 and LAMC2 has high sensitivity for BA at diagnosis and may serve as a biomarker of disease, with an important role for the IL8 signaling in experimental BA.
| S-EPMC4077977 | biostudies-literature
Project description: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.
| S-EPMC3264748 | biostudies-literature
Project description:Biliary atresia is a severe cholangiopathy of early infancy that destroys extrahepatic bile ducts and disrupts bile flow. With a poorly defined disease pathogenesis, treatment consists of the surgical removal of duct remnants followed by hepatoportoenterostomy. Although this approach can improve the short-term outcome, the liver disease progresses to end-stage cirrhosis in most children. Further improvement in outcome will require a greater understanding of the mechanisms of biliary injury and fibrosis. Here, we review progress in the field, which has been fuelled by collaborative studies in larger patient cohorts and the development of cell culture and animal model systems to directly test hypotheses. Advances include the identification of phenotypic subgroups and stages of disease based on clinical, pathological and molecular features. Stronger evidence exists for viruses, toxins and gene sequence variations in the aetiology of biliary atresia, triggering a proinflammatory response that injures the duct epithelium and produces a rapidly progressive cholangiopathy. The immune response also activates the expression of type 2 cytokines that promote epithelial cell proliferation and extracellular matrix production by nonparenchymal cells. These advances provide insight into phenotype variability and might be relevant to the design of personalized trials to block progression of liver disease.
| S-EPMC4877133 | biostudies-literature
Project description:Purpose of reviewThe purpose of this study is to review advances in both the pathogenesis and clinical management of biliary atresia.Recent findingsImmunologic studies have further characterized roles of helper T-cells, B-cells, and natural killer cells in the immune dysregulation following viral replication within and damage of biliary epithelium. Prominin-1-expressing portal fibroblasts may play an integral role in the biliary fibrosis associated with biliary atresia. A number of genetic polymorphisms have been characterized as leading to susceptibility for biliary atresia. Postoperative corticosteroid therapy is not associated with greater transplant-free survival. Newborn screening may improve outcomes of infants with biliary atresia and may also provide a long-term cost benefit.SummaryAlthough recent advances have enhanced our understanding of pathogenesis and clinical management, biliary atresia remains a significant challenge requiring further investigation.
| S-EPMC4447429 | biostudies-literature