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Delineation of the Genome-Wide Recruitment of Hepatitis B Virus Trans-Activator Protein Hbx, in Primary Hepatocytes and Liver Cancer Cells

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Delineation of the Genome-Wide Recruitment of Hepatitis B Virus Trans-Activator Protein Hbx, in Primary Hepatocytes and Liver Cancer Cells Delineation of the Genome-wide Recruitment of Hepatitis B Virus Trans-activator Protein HBx, in Primary Hepatocytes and Liver Cancer Cells By Amanda Jayne Lyon B.S. in Biomedical Technology, May 2006, Norwich University M.S. in Public Health Microbiology, Emerging Infectious Diseases, May 2009 The George Washington University A Dissertation submitted to The Faculty of The Columbian College of Arts and Sciences of The George Washington University in partial fulfillment of the requirements for the degree of Doctor of Philosophy August 31, 2012 Dissertation directed by: Rakesh Kumar Professor of Biochemistry and Molecular Biology The Columbian College of Arts and Sciences of The George Washington University certifies that Amanda Jayne Lyon has passed the Final Examination for the degree of Doctor of Philosophy as of August 7, 2012. This is the final and approved form of the dissertation. Delineation of the Genome-wide Recruitment of Hepatitis B Virus Trans-activator Protein HBx, in Primary Hepatocytes and Liver Cancer Cells. Amanda Jayne Lyon Dissertation Research Committee: Rakesh Kumar, Chairman and Professor of Biochemistry and Molecular Biology Paul J. Brindley, Professor of Microbiology, Immunology and Tropical Medicine Ajit Kumar, Professor of Biochemistry and Molecular Biology ii © Copyright “2012” by Amanda Jayne Lyon All Rights Reserved iii Dedication I would like to dedicate this dissertation to my family members; Cherie Lyon, David Lyon, Laurie Lyon, and Shaina Lyon, as well as to my Fiancée, Dirk Vandeveer. You are all instrumental in my life and have always been encouraging and supportive, thank you. iv Acknowledgements I would like to express my gratitude towards everyone who played a role in this experience, to include all of the professors and members of IBS as well as those who contributed to my dissertation research. I would like to thank Dr. Rakesh Kumar and my committee members Dr. Paul Brindley, Dr. Ajit Kumar, Dr. Jeyanthy Eswaran and Dr. Anton Sidawy, for their guidance and support throughout this experience. I am grateful for the opportunity to work on this interesting research project, which has taught me numerous skills that I will take with me. Thank you to all members of Dr. Kumar’s laboratory for your suggestions and guidance. Thank you, Dr. Ali Ramezani, for your help with the lentiviral vectors and Dr. Krishna Banudha for your help with the PHHs. Thank you to everyone who supported me in the completion of this dissertation research project, your assistance is greatly appreciated. I would like to thank Dr. Linda Werling for her support and guidance. Dr. Werling, you are a wonderful person who truly cares for her students and whose leadership in IBS makes the program so successful. Thank you to my Academic Advisor, Dr. David Leitenberg who has always been helpful and supportive. I must thank Dr. Dante Verme who was one of my very first professors at GWU, in the Fall of 2007. You are an outstanding professor and I enjoyed my time as your Graduate Administrative Assistant and Instructional Assistant for GIS. I will miss it. v Thank you to my friends in the IBS, especially the entering class of the Fall of 2009. Thank you to Claire Hoptay, Lindsay Garvin, and Amanda Woerman, who have become close friends of mine. Thank you Ngoc-Han Ha, for your friendship and support throughout this experience, and beyond. Thank you for listening, and for your advice. I will always remember the good times. At the beginning of the Ph.D., I was told that a strong support system is vital to a student’s success. Luckily, I never had to worry about that, and it is due to my amazing family and Fiancée. Mom, you always told me that I could be whatever I wanted to be, and that advice has kept me striving for more. Thank you for lending an open ear when ever I needed to talk. Your support is a vital part of my success. Dad, your support has also been vital to my success. Your words of encouragement and advice often come to my mind. I have always looked up to you and have strived to work as hard, as I know you do. Laurie, “the human dictionary,” you have always been an inspirational sister, who I’ve looked up to and have strived to be like, even though, as someone who is very independent, I would never admit it. Today, I still look up to you and am proud to have you as a role model. Shaina, you are the source of laughter in our family. You make life more fun and enjoyable and I admire that. Thank you for your support and for always being there for me. To the Vandeveers, you have been like family to me, for many years now. Thank you for being so supportive and caring. You are wonderful people who I admire and look up to. Dirk, I could not have completed the M.S., or the Ph.D. without you. Your daily support and encouragement has kept me going, through it all. Our time together has made me a much happier and stronger person. Without you, my academic success would not have been possible, thank you. vi Abstract Delineation of the Genome-wide Recruitment of Hepatitis B Virus Trans-activator Protein HBx, in Primary Hepatocytes and Liver Cancer Cells Hepatocellular carcinoma (HCC) is among the top five cancers worldwide, with Hepatitis B virus (HBV)-associated HCC accounting for the majority of all cases. The cancer promoting activity of HBV is derived from one of its gene products, HBx, the primary trans-activator of cellular genes with roles in carcinogenesis. Although the contribution of HBx to HCC is firmly established, the nature of comparative genome-wide targets of HBx in primary human hepatocytes (PHH) and liver cancer cells, remains unknown, and is being investigated in the present work. Using a genome-wide chromatin immunoprecipitation (ChIP) approach, we characterized the patterns of global recruitment (and consequently, affected genes) of HBx or its mutant, deficient in binding to p65/RelA, of the NF-κB complex, in the presence or experimental depletion of a master coregulator MTA1. We found that the overall recruitment of HBx increases following an interruption in the involvement of MTA1 and/or p65/RelA, suggesting that the levels or activities of MTA1 and p65/RelA represent two major modifiers of HBx recruitment to the human genome. Special attention was placed on targets with recruitment to transcription start sites (TSS), suggesting a probable contribution of the trans-regulatory processes, in influencing the expression of the putative HBx target genes. Representative target genes with TSS recruitment were validated by PCR and DNA gel electrophoresis and with quantitative PCR for analysis of resulting altered expression in ChIP samples. This is the first high- throughput analysis of the genome-wide recruitment of HBx to characterize the involvement of a master chromatin modifier as well as a transcription factor, which act to alter the ability of HBx to trans-regulate genes that may be involved in the development of vii HBV-associated HCC. This analysis provides novel insight into the identity of targeted genes that are trans-regulated by this viral protein and elucidates how these factors may contribute to the functions of HBx, a major risk factor for the development of HCC. viii Table of Contents Dedication………………………………………………………………………………....iv Acknowledgements………………………………………………………………………...v Abstract……………………………………………………………………………..…….vii Table of Contents……………………………………………………………………...…..ix List of Figures…………………………………………………………………………….xii List of Tables ……………………………………………………………………….……xiv List of Abbreviations………………………………………………………………….…..xv Chapter 1: Introduction……………………………………………………………………..1 1.1 Hepatitis B virus and Hepatocellular Carcinoma………...….....……………….1 1.1.1 Viral Oncology and HBV…………………..……………..………………1 1.1.2 HBV and HBx…………….……………...……………………………….2 1.1.3 HBx and HCC…………………...….…………………………………….3 1.2 Host-viral Interactions Associated with HBx……...……………………….…..9 1.2.1 MTA1 and HBx…………………………..………………..……………..9 1.2.2 NF-κB, MTA1 and HBx………………..…….…………………………12 1.3 Specific Aims………………..……...…………………………………………18 Chapter 2: Materials and Methods………………………………………………………...19 2.1 Cell Lines…………….………..…………………………..…………………..19 2.2 Cloning………………………...………………………………….…………...19 2.3 Lentiviral Vectors…………………………...………………………………...20 2.4 siRNA Experiments………..…………………….……………………………20 ix 2.5 Western Blotting Analysis………………………………………………..……21 2.6 FACS Analysis and Fluorescent Microscopy…….…………………………….21 2.7 Chromatin Immunoprecipitation and Sequencing…………….……….………..22 2.8 Computational Analyses…………………..………………………………...….22 2.8.1 Avadis NGS………………………………………………………….22 2.8.2 UCSC Genome Browser…………...………………………………..23 2.8.3 Ingenuity Pathway Analysis (IPA)………..………………………...24 2.9 PCR, DNA Gel Electrophoresis, and qPCR…..………...…….………………...24 Chapter 3: Results…………………………………………………………………………26 3.1 Introduction and Experimental Model…………………….……………………26 3.1.1 Introduction…………………………..……………………………..26 3.1.2 Experimental Strategy…………………………………………….....27 3.2 Global Genome-wide Targeting of HBx and the Role of MTA1…………….....40 3.2.1 Characteristics of Binding………….……………………………….40 3.2.2 MTA1 and p65 are Central to Genome-wide Targeting by IPA Network Analysis…………………….……….……………………………46 3.2.3 Genome-wide Targeting of HBx to Chromosomes…………..……..56 3.2.4 Unfiltered Heaviest HBx Recruitment……………………………….61 3.3 MTA1 Status Alters the Ability of HBx to Target Categories of Genes……..……61 3.3.1 Molecular and Cellular Functions and Canonical Pathways of Targeted Genes……….…………...……………………………….……...61 3.3.2 HBx Recruitment to Top Nodal Points of Networks…………….....71 x 3.4 HBx
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