UC San Diego UC San Diego Electronic Theses and Dissertations Title Systems Biology of Liver Regeneration and Pathologies Permalink https://escholarship.org/uc/item/05d214b4 Author Min, Jun SungJun Publication Date 2015 Peer reviewed|Thesis/dissertation eScholarship.org Powered by the California Digital Library University of California UNIVERSITY OF CALIFORNIA, SAN DIEGO Systems Biology of Liver Regeneration and Pathologies A dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Bioengineering by Jun SungJun Min Committee in charge: Professor Shankar Subramaniam, Chair Professor Pedro Cabrales Professor Daniel Tartakovsky Professor Shyni Varghese Professor Yingxiao Wang 2015 Copyright Jun SungJun Min, 2015 All rights reserved. The Dissertation of Jun SungJun Min is approved, and it is acceptable in quality and form for publication on microfilm and electronically: ______________________________________________________________ ______________________________________________________________ ______________________________________________________________ ______________________________________________________________ ______________________________________________________________ Chair University of California, San Diego 2015 iii DEDICATION To my friends and family With their love and support iv TABLE OF CONTENTS Signature Page ..................................................................................................... iii Dedication ............................................................................................................ iv Table of Contents .................................................................................................. v List of Figures ...................................................................................................... vii List of Tables ...................................................................................................... viii List of Supplemental Figures ................................................................................ ix List of Supplemental Tables .................................................................................. x Acknowledgements .............................................................................................. xi Vita ..................................................................................................................... xiv Abstract of the Dissertation ................................................................................. xv Introduction ........................................................................................................... 1 CHAPTER 1: SYSTEMS BIOLOGY OF LIVER REGENERATION WITH Chapter 1: TRANSCRIPTOMIC AND METABOLOMIC ANALYSES ............... 6 wtfs Abstract .......................................................................................................... 6 wtfs Introduction .................................................................................................... 7 wtfs Methods ....................................................................................................... 10 wtfs Results ......................................................................................................... 16 wtfs Discussion .................................................................................................... 30 v wtfs Supplementary Materials ............................................................................. 39 wtfs Acknowledgements ...................................................................................... 63 CHAPTER 2: TRANSCRIPTOMIC AND INTEGRATIVE ANALYSES OF CHAPTER 2: BILIARY ATRESIA ....................................................................... 64 wtfs Introduction .................................................................................................. 64 wtfs Methods ....................................................................................................... 66 wtfs Results ......................................................................................................... 70 wtfs Discussion .................................................................................................... 88 wtfs Supplementary Materials ............................................................................. 94 wtfs Acknowledgements .................................................................................... 116 CHAPTER 3: TARGET SEQUENCING, EXOME SEQUENCING, AND CHAPTER 3: NETWORK ANALYSES OF BILIARY ATRESIA ........................ 117 wtfs Introduction ................................................................................................ 117 wtfs Methods ..................................................................................................... 121 wtfs Results ....................................................................................................... 127 wtfs Discussion .................................................................................................. 139 wtfs Supplementary Materials ........................................................................... 146 wtfs Acknowledgements .................................................................................... 166 Conclusion ........................................................................................................ 167 References ....................................................................................................... 170 vi LIST OF FIGURES Figure 1.1 Venn diagrams of differentially regulated genes after PHx under the p-value cutoff of 0.05 and the FDR cutoff of 0.1 and over-represented biological functions and pathways during the priming phase ......................................................... 18 Figure 1.2 Temporal network analysis in Cytoscape ................................. 21 Figure 1.3 Acute phase genes after partial hepatectomy .......................... 22 Figure 1.4 Temporal gene expression of the acute phase proteins and their correlation with cytokine profiles ...................................... 23 Figure 1.5 Transcriptomic and metabolic profiles for cholesterol metabolism ............................................................................... 26 Figure 1.6 Metabolic fold changes at 3 hours and the heatmap of lipid metabolic genes ....................................................................... 29 Figure 1.7 Correlation heatmap of gene-metabolite pairs in the sterol pathway.................................................................................... 30 Figure 1.8 Proposed mechanism of the priming phase of complement- induced liver regeneration ........................................................ 37 Figure 2.1 Workflows for the transcriptomic and the integrative analyses ................................................................................... 70 Figure 2.2 Distribution of RNAseq read counts in BA ............................... 71 Figure 2.3 RNAseq dispersion plot ........................................................... 72 Figure 2.4 Differentially regulated genes in enriched biological categories ................................................................................ 78 Figure 2.5 Enriched KEGG pathways ....................................................... 80 Figure 2.6 Sequence features of significant GWAS variants ..................... 86 Figure 3.1 Novel systems biology approach for the reconstruction of the BA network ............................................................................. 120 Figure 3.2 Linkage disequilibrium analysis of exon #7 of MAN1A2 ......... 130 Figure 3.3 Whole exome network ........................................................... 134 Figure 3.4 Proposed biliary atresia network ............................................ 136 Figure 3.5 Common biological functions in the proposed biliary atresia network .................................................................................. 137 vii LIST OF TABLES Table 2.1 List of differentially regulated genes ......................................... 73 Table 2.2 Enriched Gene Ontology terms ................................................ 77 Table 2.3 Enriched KEGG pathways ....................................................... 80 Table 2.4 Differentially regulated genes in the complement and coagulation cascade ................................................................ 81 Table 2.5 Differential regulation of exons in MAN1A2 ............................. 82 Table 2.6 Differential alternate splicing in MAN1A2 ................................. 83 Table 2.7 Significant pairs of differentially regulated genes and BA- associated SNPs ...................................................................... 84 Table 2.8 eQTL results from the second integrative analysis .................. 87 Table 2.9 Functional prediction of unassociated SNPS ........................... 88 Table 3.1 Recent biliary atresia GWAS studies ..................................... 118 Table 3.2 Average alignment metrics for target and whole exome sequencing............................................................................. 127 Table 3.3 Novel SNPs from target sequencing ...................................... 128 Table 3.4 Novel missense SNPs from whole exome ............................. 131 Table 3.5 Top 5 common transcription factors from the BA network ..... 138 viii LIST OF SUPPLEMENTAL FIGURES Figure S1.1 Correlation plot between