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Roles of the Snf2-Like Helicase Hells in Myc-Driven Gene Transcription

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Roles of the Snf2-Like Helicase Hells in Myc-Driven Gene Transcription ROLES OF THE SNF2-LIKE HELICASE HELLS IN MYC-DRIVEN GENE TRANSCRIPTION by Jane A. Welch A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, MD October 2017 © Jane A. Welch 2017 All Rights Reserved Abstract Helicase, lymphoid specific (HELLS) is a SNF2-like ATP-dependent chromatin remodeler that participates in transcriptional repression and activation in mammalian cells (von Eyss et al., 2012; Myant and Stancheva, 2008). HELLS has long been described as a proliferation-associated protein (Jarvis et al., 1996; Lee et al., 2000; Raabe et al., 2001), but its role in neoplastic diseases, which are characterized by cellular hyperproliferation, has not been widely investigated. This dissertation presents work that addresses how the expression and molecular function of HELLS may have pathologic relevance to human cancers. Through immunohistochemistry and RNA sequencing (RNA-seq), we found that HELLS is abundantly expressed in proliferative compartments of normal human tissues and broadly overexpressed in a number of cancers. We used chromatin immunoprecipitation followed by sequencing (ChIP-seq) to identify HELLS binding sites in human Burkitt lymphoma, glioblastoma multiforme, and small cell lung carcinoma cell line genomes and found that HELLS predominantly targets the promoters of transcribed genes, leading us to conclude that in human cancers, HELLS function is likely to be associated with transcriptional activation rather than repression. Expressed HELLS-bound genes are significantly enriched for targets of MYC, which has well-described oncogenic effects. Using ChIP- seq and co-immunoprecipitation (co-IP), we found that HELLS and MYC colocalize extensively at transcribed gene promoters and physically interact in human cells, which ii suggests that the proteins may functionally interact as well. We modeled partial loss of HELLS function in human cells through CRISPR/Cas9-mediated engineering of a hypomorphic HELLS allele and found that genes previously identified as HELLS targets exhibited altered expression levels. In human osteosarcoma cells with inducible MYC, we tested the effects of RNA interference (RNAi)-induced HELLS knockdown on MYC- driven transcription. While MYC target gene induction was not wholly impaired, a subset of MYC targets exhibited decreased expression. We conclude that HELLS is a bona fide MYC-interacting protein that may contribute to regulating the expression of some MYC targets, which could have implications for human tumor biology. Thesis advisor: Kathleen H. Burns, M.D., Ph.D. Thesis readers: Kathleen H. Burns, M.D., Ph.D. and Kirby D. Smith, Ph.D. iii Acknowledgements It is often said that it takes a village to raise a child. In my opinion, it also takes a village to raise a scientist at the doctoral level. I helmed my research projects, designed and conducted experiments with my own two hands, prepared my own presentations for meetings and conferences, and wrote this dissertation, but I could not have accomplished any of these things without the support of many others. I will begin by thanking the faculty and staff of the Predoctoral Training Program in Human Genetics housed in the McKusick-Nathans Institute of Genetic Medicine, especially Dr. David Valle and Sandy Muscelli. Earning acceptance into this program became my dream early on in my undergraduate studies. I am so very grateful that I was given the opportunity to study and train in this program, and I will always strive to be a positive reflection of it. I feel that receiving mentorship from my thesis advisor, Dr. Kathleen Burns, has made me one of the luckiest trainees at this institution. Kathy has enthusiastically supported me as I pursued both scientific questions of interest and professional development opportunities. She has always believed in me, even during the times when I found it impossible to believe in myself. She is the most gracious and considerate professional I have ever had the privilege to work with, and I will always look to her as a role model. I will be eternally grateful for the experience of being her mentee. iv During my graduate studies, I have also had the privilege to work with a number of talented and generous collaborators on my projects: Dr. Amy Duffield at the Johns Hopkins Hospital’s clinical IHC laboratory; Daniel Ardeljan, Dr. Kathy Burns, David Esopi, Dr. Michael Haffner, Dr. Chunhong Liu, Dr. Paul Schaughency, Alyza Skaist, Reema Sharma, Peilin Shen, Dr. Sarah Wheelan, William Wu, and Dr. Srinivasan Yegnasubramanian here at the Johns Hopkins University School of Medicine; Dr. Brian Altman, Dr. Annie Hsieh, and Dr. Chi Dang, who worked together at the University of Pennsylvania during our time of collaboration; and Dr. David Fenyö, Zuojian Tang, and Xuya Wang at the New York University School of Medicine. The work presented in this dissertation would not have been possible without their collaboration, and it is for that reason that I use “we” in presenting the rationales for experiments, hypotheses, findings, and conclusions throughout this tome. I would like to thank the members of my thesis committee– Dr. Kathy Burns, Dr. Elana Fertig, Dr. Haig Kazazian (my committee chairman), Dr. Kirby Smith, Dr. Sarah Wheelan, and Dr. Srinivasan Yegnasubramanian– for the thoughtful discussions, constructive criticisms, and steadfast encouragement they have provided over the past several years. I am especially grateful that Kathy and Kirby were willing to read this lengthy thesis and offer suggestions for improvement. I am very grateful to have worked alongside my colleagues, both former and current, in the Burns lab for all these years. They have always been generous with offering feedback on my experiments and analyses, and I have learned a great deal by working with them. In particular, I would like to thank Dan Ardeljan, Dr. Chunhong Liu, v Reema Sharma, Peilin Shen, and William Wu for collaborating with me on several of my projects. I am also incredibly grateful to Dr. Sarah Wheelan and the members of her lab– particularly Dr. Bracha Avigdor, Lauren Ciotti, Dr. Paul Schaughency, Alyza Skaist, and Heather Wick– for working closely with me during much of my time here at the School of Medicine. Sarah co-mentored me for many years, and it is entirely thanks to her and her lab members that I learned enough programming to complete the bioinformatics components of my thesis work. I would like to thank everyone at OMIM®, especially Joanna Amberger, Dr. Nara Sobreira, Matt Gross, and Carol Bocchini, for giving me the opportunity to write for their organization. I wholeheartedly believe that reviewing journal articles and drafting gene entries for OMIM® have made an important contribution to my education as a scientist. I feel that I would be remiss if I did not acknowledge Dr. Kerry Smith and Dr. Cheryl Ingram-Smith, who welcomed me into their laboratory as a completely inexperienced rising freshman at Clemson University. My dearest ambition was– and still is today– to find a way to help others through my work. Kerry and Cheryl taught me that research could provide a way to achieve that ambition, as our efforts to understand the bases of human diseases can ultimately lead us to ways to help people who are suffering. Without their guidance and support, I am not sure that I would ever have taken the path to becoming a biomedical scientist. As such, I will always be grateful to them both. Last, but unequivocally not least, I am incredibly grateful to my family and friends for their unwavering support throughout my lifetime and, in particular, during the vi long, challenging process of earning my Ph.D. My parents, Rob and Anne Welch, and their personal experiences with genetic disorders were really what sparked my interest in human genetics at a pretty early age. They have done everything they possibly could have to foster this interest of mine and to help me achieve my dream of becoming a geneticist, and I will always, always be thankful to them. My brother, David, has also been a substantial source of encouragement, along with my wonderful and loveable extended family: Jim and Pam Welch; Rosemary Nellist; Terry and Beth Dismukes; Matt, Sonia, Cannon, Chandler, and Saylor Dismukes; Jim, Ginnie, and Michelle Dismukes; Lauren and Jimmy Marshall; Bobby Dismukes and Jim White; Glenn, Adam, Jessica, and Dr. Joey Dismukes; and Brian and Will Dismukes. I have no doubt that my late grandparents, James and Laureign Welch and John and Doris Dismukes, would have been incredibly supportive and very proud of me for taking on the challenge of earning a Ph.D.– especially my Grandma Welch, who strongly advocated for women’s education. I would also like to offer heartfelt thanks to my dear friends; Randy, Becky, and Zach Hawkins; Rico, Sikithea, Skylar, and Sydney Zackery; and Nichola, Griffin, and Jillie Conze for all their love and support. In particular, Skylar, Sydney, and Nichola have brought me so much joy and encouragement, and they have made my hardest days so much easier to bear. Finally, I want to acknowledge my beloved collie, Toby, for always being able to make me smile– and for always reminding me of what matters most in life. vii Table of Contents Abstract ii Acknowledgements iv Table of Contents viii List of Figures xv List of Tables xx Chapter 1 Introduction 1 1.1 SWI/SNF chromatin remodelers and gene expression 1 1.2 Discovery and early characterization of HELLS 2 1.3 HELLS-associated phenotypes 4 1.4 Transcriptional regulation by
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