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Investigation of Chd7 Function in Developmental Models Of INVESTIGATION OF CHD7 FUNCTION IN DEVELOPMENTAL MODELS OF CHARGE SYNDROME by STEPHANIE ANN BALOW Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation advisor: Peter C. Scacheri, Ph.D. Department of Genetics and Genome Sciences CASE WESTERN RESERVE UNIVERSITY May 2014 To my parents, for their constant love and support ! "! Table of Contents List of tables!!!!!!!!!!!!!!!!!!!!!!!!!!!.... 4 List of figures!!!!!!!!!!!!!!!!!!!!!!!!!!!.. 5 Acknowledgements!!!!!!!!!!!!!!!!!!!!!!!!... 7 Abstract!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 9 Chapter 1: Introduction and Background!!!!!!!!!!!!!!.. 11 Overview of chromatin remodeling and development!!!!!!!!12 Chromodomain helicase DNA-binding (CHD) protein family!!!!!13 Subfamily I: CHD1 and CHD2!!!!!!!!!!!!!!...13 Subfamily II: CHD3, CHD4, and CHD5!!!!!!!!!!!15 Subfamily III: CHD6, CHD7, CHD8, and CHD9!!!!!!!. 17 CHD7!!!!!!!!!!!!!!!!!!!!!!!!!!!! 18 Molecular function of the CHD7 protein!!!!!!!!!!...18 Expression of CHD7 during development!!!!!!!!!. 22 CHARGE syndrome!!!!!!!!!!!!!!!!!!!!!!23 Overview!!!!!!!!!!!!!!!!!!!!!!!.. 23 Expansion of the CHARGE syndrome clinical presentation!! 23 Ocular coloboma!!!!!!!!!!!!!!!!!.24 Heart defects!!!!!!!!!!!!!!!!!!.. 24 Choanal atresia!!!!!!!!!!!!!!!!!.. 24 Growth retardation!!!!!!!!!!!!!!!!. 25 Genital abnormalities!!!!!!!!!!!!!!!. 25 Ear anomalies!!!!!!!!!!!!!!!!!!. 26 Other common phenotypes!!!!!!!!!!!!.. 26 Mutation spectrum!!!!!!!!!!!!!!!!!!!. 27 Clinical overlap with other syndromes!!!!!!!!!!! 28 Animal models of CHARGE syndrome!!!!!!!!!!...29 Regulation of rDNA expression!!!!!!!!!!!!!!!!....31 The nucleolus and building a ribosome!!!!!!!!!!...32 Structure and transcriptional regulation of rDNA!!!!!!!32 Epigenetic regulation of rDNA repeats!!!!!!!!!!....35 FBXL10 is an epigenetic modifier of rDNA expression!!!.....36 Dysregulation of ribosome biogenesis!!!!!!!!!!!!!.!39 The nucleolar stress response!!!!!!!!!!!!!!..39 Ribosomopathies!!!!!!!!!!!!!!!!!!!.!43 Summary and Research Aims!!!!!!!!!!!!!!!!!...46 Chapter 2: Knockdown of fbxl10/kdm2bb rescues chd7 morphant phenotype in a zebrafish model of CHARGE syndrome!!!!!!...!..49 Abstract!!!!!!!!!!!!!!!!!!!!!!!!!...!...50 Introduction!!!!!!!!!!!!!!!!!!!!!!!!...!.52 Results!!!!!!!!!!!!!!!!!!!!!!!!!!...!.55 Organization of the zebrafish chd7 gene!!!!!!!!!......55 chd7-morpholino gene targeting recapitulates major features of CHARGE syndrome!!!!!!!!!!!!!!!!!!.55 ! #! chd7 morphants develop defects in neural crest-derived craniofacial cartilage!!!!!!!!!!!!!!!!!!..63 Chd7 is required for normal cellular proliferation during zebrafish development!!!!!!!!!!!!!!!!!..68 Fbxl10 regulates rRNA levels during zebrafish embryogenesis!!!!!!!!!!!!!!!!!!!!...72 Rescue of chd7 morphant phenotype upon knockdown of fbxl10!!!!!!!!!!!!!!!!!!!!!!!!...76 Analysis of rRNA and cell cycle genes in fbxl10/chd7 double morphants!!!!!!!!!!!!!!!!!!!!!!...84 Discussion!!!!!!!!!!!!!!!!!!!!!!!!!...87 Materials and methods!!!!!!!!!!!!!!!!!!!!..91 Chapter 3: Dissecting CHD7 functions in a human iPS cell model of CHARGE syndrome..!!!!!!!!!!!!!!!!!!!!!!!..98 Introduction!!!!!!!!!!!!!!!!!!!!!!!!!.99 Results!!!!!!!!!!!!!!!!!!!!!!!!!!...102 Early characterization and preliminary data in CHARGE syndrome patient-derived iPS cells!!!!!!!.102 Discussion!!!!!!!!!!!!!!!!!!!!!!!!!..111 Materials and methods!!!!!!!!!!!!!!!!!!!!.114 Chapter 4: Discussion and future directions!!!!!!!!!!!!..117 Summary!!!!!!!!!!!!!!!!!!!!!!!!!!118 Discussion and future directions!!!!!!!!!!!!!!!!120 Implications of zebrafish chd7 morphant model studies!!!120 Does chd7 regulate cellular proliferation in specific tissues?..........................................................................120 What is the molecular mechanism of chd7 morphant rescue by fbxl10 knockdown!!!!!!!!!!!...121 Are these findings applicable to mammalian development?.................................................................125 Future experiments investigating the nucleolar and nuclear functions of CHD7 using iPS cells as a developmental model of CHARGE syndrome!!!!!!!..126 Summary remarks!!!!!!!!!!!!!!!!!!!!!....132 Bibliography!!!!!!!!!!!!!!!!!!!!!!!!!!....134 ! $! List of tables Chapter 2 Table 2-1. CHD7 mutant phenotypes comparison across multiple species!!!!!!!!!!!!!!!!!!!!!!!.62 Table 2-2. PCR primers designed to measure gene expression!!!!!97 ! %! List of figures Chapter 1 Figure 1-1. Members of the CHD family!!!!!!!!!!!!!!!..14 Figure 1-2. Simple schematic of a single mouse rDNA gene!!!!!!..34 Figure 1-3. Schematic of FBXL10 protein domain composition!!!!!..37 Figure 1-4. Overview of the nucleolar stress response!!!!!!!!!40 Figure 1-5. Disruption of ribosomal biogenesis alters nucleolar structure resulting in the stabilization of p53!!!!!!!!!!!..42 Chapter 2 Figure 2-1. Morpholino targeting of the zebrafish chd7 RNA induces an aberrant transcript!!!!!!!!!!!!!!!!!!..56 Figure 2-2. Zebrafish chd7 targeting results in CHARGE-like phenotypes!!!!!!!!!!!!!!!!!!!!!..60 Figure 2-3. chd7 morphants display variable defects in craniofacial cartilage!!!!!!!!!!!!!!!!!!!!!!...64 Figure 2-4. Sectioning of chd7 morphants reveals moderate to severe craniofacial cartilage abnormalities!!!!!!!!!!!.66 Figure 2-5. chd7 targeting impairs cellular proliferation!!!!!!!!...69 Figure 2-6. Targeting of zebrafish fbxl10 transcript modulates pre-rRNA expression!!!!!!!!!!!!!!!!!!!!!...73 Figure 2-7. Modulation of fbxl10 expression results in normal development of gross anatomical and craniofacial structures!!!!!!..........................................................75 Figure 2-8. Modulation of fbxl10 expression rescues CHARGE-like phenotypes and improves cellular proliferation defects.!!.77 Figure 2-9. Changes in cellular proliferation correlate with embryonic head size!!!!!!!!!!!!!!!!!!!!!!79 Figure 2-10. Sagittal sectioning of 4 dpf chd7/fbxl10 double morphants indicates variable restoration of ceratobranchial cartilage development!!!!!!!!!!!!!!!!!!!!..82 ! &! Figure 2-11. Gene expression changes in cell-cycle regulators in chd7/fbxl10 double morphants!!!!!!!!!!!!!85 Chapter 3 Figure 3-1. The locations of CHD7 mutations in CHARGE syndrome patient-derived iPS cell lines!!!!!!!!!!!!!..103 Figure 3-2. Reprogrammed CHARGE syndrome patient cells express multiple markers of pluripotency!!!!!!!!!!!....105 Figure 3-3. CHD7 expression is significantly reduced in CHARGE syndrome patient-derived iPS cells!!!!!!!!!.!..106 Figure 3-4. CHD7 protein localizes to different cell sub-compartments in different cell types!!!!!!!!!!!!!!!!....109 Figure 3-5. Decreases in CHD7 expression do not affect 45S pre-rRNA expression in iPS cells!!!!!!!!!!!!!!!....110 Chapter 4 Figure 4-1. Model of interactions potentially involved in molecular mechanism of rescue in chd7/fbxl10 double morphants!....123 Figure 4-2. Multiple histone tail modifications demarcate enhancer activity and expression of target genes!!!!...................130 ! '! Acknowledgments First and foremost, I would like to thank my advisor, Peter Scacheri, for his expertise, guidance, and his commitment to my success. My time in his laboratory has been invaluable and has helped me build strong skill sets both at the bench and in communication. It has been clear over these past 5 years that he has a vested interest in my well-being, and I appreciate this immensely. I am truly grateful for all his help, patience, and encouragement, which have helped mold me into a more confident and independent scientist. I would also like to thank my committee members Ron Conlon, Peter Harte, and Brian McDermott for their support and encouragement throughout my graduate career. They continuously provided vital outside perspective to my project by asking questions and providing suggestions. I am also indebted to our collaborator, Paul Tesar, for his help and advice. I would also like to extend my thank you to the entire departmental faculty and administrative staff. I truly believe that my interactions with the faculty over the years, whether in the classroom or casually in the hallway, have been vital in shaping my progress. I would also like to thank the past and present members of the Scacheri laboratory, as without them, none of this would be possible. Although everyone has been a great source of camaraderie both personally and scientifically, there are three members that I would like to especially thank. I am particularly indebted to Cindy Bartels for her technical support and her overall willingness to drop everything to help me in times of need. I would also like to thank Olivia Corradin, who for the past several years, has not only been my baymate but also a good ! (! friend. She is always a constant source of positivity and has always been willing to listen and discuss. Lastly, I am beyond grateful for my friendship with my previous baymate and “lab brother”, Gabe Zentner. I owe him more than I can say for the scientific discussions that helped shaped the beginnings of this project and also for his mental support along the way. Furthermore, I would like to thank my friends from both here and afar for all their support. I would like to especially thank my best friend, Meghana Gupta. We met during the first week of graduate school orientation and I could not have been luckier to have met such a loyal and caring friend. She has been there for me in the best and worst of times over the years and, without her, I think I would have lost my sanity ages ago. I would also like to thank my dear friends Jason Heaney, Lorrie Rice, Meetha Gould,
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