Systems Analysis of Biliary Atresia Through Integration of High-Throughput Biological Data.

Jun Min,Juhoon So,Shankar Subramaniam,Donghun Shin,Mylarappa Ningappa,Rakesh Sindhi

doi:10.3389/fphys.2020.00966

Abstract

Biliary atresia (BA), blockage of the proper bile flow due to loss of extrahepatic bile ducts, is a rare, complex disease of the liver and the bile ducts with unknown etiology. Despite ongoing investigations to understand its complex pathogenesis, BA remains the most common cause of liver failure requiring liver transplantation in children. To elucidate underlying mechanisms, we analyzed the different types of high-throughput genomic and transcriptomic data collected from the blood and liver tissue samples of children suffering from BA. Through use of a novel integrative approach, we identified potential biomarkers and over-represented biological functions and pathways to derive a comprehensive network showing the dysfunctional mechanisms associated with BA. One of the pathways highlighted in the integrative network was hypoxia signaling. Perturbation with hypoxia inducible factor activator, dimethyloxalylglycine, induced the biliary defects of BA in a zebrafish model, serving as a validation for our studies. Our approach enables a systems-level understanding of human BA biology that is highlighted by the interaction between key biological functions such as fibrosis, inflammation, immunity, hypoxia, and development.

Highlights

Biliary atresia (BA), or absence of extrahepatic ducts, which drain bile outside the liver, is a rare condition whose pathogenesis must be understood in order to limit its significant public health impact
Most of the genes in the chemokine signaling pathway, including chemokine (C-X-C motif) ligand 5 (CXCL5) and interleukin 8 (IL8), showed significant upregulation in their transcripts (Figure 2A). Inflammatory genes showed both up- and downregulation; many pro-inflammatory chemokines including IL8 were upregulated while some acute inflammatory genes, orosomucoid 1 (ORM1), serum amyloid A1 (SAA1), and serum amyloid A2 (SAA2), were downregulated in the BA group (Figure 2B)
The proposed BA network has several advantages over existing postulated mechanisms: (i) the network can be used to study both the individual interactions among specific genes and the complex relationship among the major hubs of genes involved in fibrosis, immunity, inflammation, hypoxia, and development; (ii) the network is highly trainable; future experiments could refine the genes and their individual interactions from the existing version of the network; (iii) the network contains the variants with high allele frequency, which ensures a high degree of confidence and replicability; (iv) common biological functions, such as inflammation, regulation of immune response, and embryonic development, were shared between the proposed BA network and the whole exome network

Summary

Introduction

Biliary atresia (BA), or absence of extrahepatic ducts, which drain bile outside the liver, is a rare condition whose pathogenesis must be understood in order to limit its significant public health impact. Systems Analysis of Biliary Atresia signature in BA-affected human liver tissues (Honsawek et al, 2005), and multiple susceptibility genes identified in genomewide association studies in BA (Ningappa et al, 2015). While the complex pathogenesis of BA requires critical evaluation, we face clinical and experimental challenges. Because the disease manifests at birth, investigating the role of various factors would require sequential evaluation of fetal and perinatal liver tissues, a task that poses ethical and technical challenges in humans. Modeling the interaction between different potential etiologic factors in an animal model is difficult in the presence of combinatorial effects of multiple susceptibility genes and unknown extraneous triggers required for disease onset and progression (Nakamura and Tanoue, 2013; Ningappa et al, 2015)

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Conclusion