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Intrinsic and Extrinsic Regulation of Mecp2 in Brain Cell Types and Their

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Intrinsic and Extrinsic Regulation of Mecp2 in Brain Cell Types and Their Intrinsic and Extrinsic Regulation of MeCP2 in Brain Cell Types and Their Implications in MeCP2-Related Neurodevelopmental Disorders By Vichithra Rasangi Batuwita Liyanage A thesis submitted to the Faculty of Graduate Studies of The University of Manitoba In partial fulfillment of the requirements of the degree of DOCTOR OF PHILOSOPHY Department of Biochemistry and Medical Genetics Rady Faculty of Health Sciences University of Manitoba Winnipeg, Manitoba, Canada Copyright © 2017 by Vichithra Rasangi Batuwita Liyanage THESIS ABSTRACT MeCP2 is a key epigenetic regulator in the brain, which regulates gene expression. There are two Mecp2/MeCP2 isoforms - MeCP2E1 and MeCP2E2 - with both overlapping and non- overlapping expression and functions in the brain. MeCP2 is widely expressed in different brain cell types but predominantly expressed in neurons. MECP2/MeCP2-deficiency and overexpression are associated with Rett Syndrome (RTT), MECP2 duplication syndrome (MDS) and alcohol (ethanol)-mediated neurological damage, such as Fetal Alcohol Spectrum Disorders (FASD). These disorders have no cure. Rescuing the expression levels of MeCP2 could be a potential therapeutic approach for these diseases. A thorough understanding of MeCP2 expression regulation is essential to achieve this goal. The objective of my Ph.D. project presented in this thesis is to address the knowledge gap on Mecp2 regulation in the brain, which has been carried out using cellular models of in vitro neural stem cell (NSC) differentiation and in vivo differentiated neurons and astrocytes. As such, the intrinsic regulation of Mecp2 isoforms by epigenetic and transcriptional mechanisms, and extrinsic regulation of Mecp2 isoforms by the insult of ethanol exposure were explored in this thesis. We identified six regulatory elements (REs) within the Mecp2 promoter and intron 1, DNA methylation of which correlated with the expression of Mecp2 isoforms during NSC differentiation [Liyanage et al. (2013), Molecular Autism]. The role of DNA methylation in Mecp2 regulation was studied by treatment with a DNA demethylating agent decitabine, which was identified as a potential drug that induces Mecp2/MeCP2 expression in an isoform-specific manner. In terms of the extrinsic regulation by ethanol, dynamic DNA methylation patterns at these REs was associated with the alterations of Mecp2 levels by ethanol exposure and withdrawal during NSC differentiation [Liyanage et al. (2015), Experimental Neurology]. We also found that expression i of Mecp2 isoforms in primary neurons and astrocytes is cell type- and sex-specific. The higher expression of Mecp2 isoforms in neurons as compared to astrocytes is possibly mediated through lower DNA methylation levels in these identified REs. Taken together, my studies provide evidence for the role of DNA methylation in epigenetic regulation of Mecp2 in these brain cells, under normal conditions and in response to extrinsic deregulation by ethanol exposure. The ability of the DNA methylation inhibitor decitabine to upregulate Mecp2 levels provides insights on potential future drug treatment strategies for MeCP2- deficiency-associated neurological conditions. The knowledge gained from this study will hold promise for utilizing these intrinsic and extrinsic regulatory mechanisms of Mecp2 isoforms for a better understanding of diseases pathology and provides insights into translational knowledge on further MeCP2 research and therapy strategies for MeCP2-associated neurological disorders. ii ACKNOWLEDGEMENTS It has been a long six years during which I experienced and embraced victory, success, many achievements as well as challenges, failures, and pain. I am indebted to all who were there for me, who helped me and encouraged me. First and foremost, my deepest gratitude is offered to my supervisor Dr. Mojgan Rastegar. The guidance and opportunities you provided were invaluable for my progress as a graduate student. I am proud to be one of your students, and any student would be lucky to have you as their mentor. Secondly, I extend my thanks to my advisory committee members, Dr. Jim Davie, Dr. John Wilkins and Dr. Chris Anderson. Over the last six years, there were numerous individual and group meetings to revise my project. Your input and guidance, as well as the faith you had in me, are deeply appreciated. I especially thank Dr. Jim Davie, whom I consider as a second mentor to me. From the days that I participated in your Gene Expression classes, I idealized you as a scientist I want to be one day. Special thanks go to my external thesis examiner Dr. Vince Tropepe. Thank you very much for your insightful comments. They had a significant impact on my perspectives on my thesis studies. Dr. Louise Simard, the Head of the Department of Biochemistry and Medical Genetics, I am indebted to you for your kindness, empathy, guidance and mentorship during the most difficult period of my life. I learned a lot from you. You are and will always be an inspiration to me. I owe my heartfelt appreciation to the Chairs of Graduate Student Affairs, Dr. Leigh Murphy, Dr. Mark Nachtigal and Dr. Jeff Wigle. Rastegar lab was a friendly environment, where I considered as a second home and worked hard day and night for six years. I am highly appreciative of the impacts it had on my life. Carl iii Olson, you are awesome! Since the day I joined Rastegar lab, you have been a great help. My previous lab member Benjamin Arthur Barber (King Arthur) made the stressful graduate life quite fun. I also would like to thank other lab members, who helped me in various ways. Special thanks go to Romina Levy, who helped me with some of the experiments. I would like to thank Dr. Barbara Triggs-Raine for letting me use the ‘special’ PCR machine for my experiments. I thank the office staff of the Department of Biochemistry and Medical Genetics, including Mrs. Tuntun Sarkar, Mrs. Cathy Webber and Mr. Philip Dufresne who helped me on various occasions regarding matters related to graduate studies. I highly appreciate the financial supports of Manitoba Health Research Council/Research Manitoba and University of Manitoba Graduate Studentship, which provided my stipend from 2011-2017, and my stipend top-ups from Dr. Rastegar grants (NSERC Discovery Grant, CIHR Catalyst/Team Grant, and the Graduate Enhancement of Tri-Council Stipends (GETS)). Additionally, I am thankful to the Department of Biochemistry and Medical Genetics and Faculty of Graduate Studies for various awards that contributed towards my tuition. I take this opportunity to thank all the funding agencies that supported my research work at the Rastegar lab. The research reported in this thesis was funded by the Natural Sciences and Engineering Research Council of Canada (NSERC Discovery Grant 372405–2009), Scottish Rite Charitable Foundation of Canada (SRCFC, Grant 10110), the Health Sciences Center Foundation (HSCF), and the Canadian Institute of Health Research (CIHR) Catalyst Grant (CEN-132383). During the last two years of my Ph.D. studies, I fell severely ill. There were a handful of people who supported me, encouraged me and helped me to ease my pain. Molly, Santhosh, Pratima and Sumanta, I am so thankful for all your kindness and empathy. The accessibility/disability services of the University of Manitoba and Mr. Jamie Penner who was my iv accessibility advisor during this time helped me immensely. Words fail to express my gratitude to you. Big thanks go to my ‘gang’ Ariff, Kannan, Vasu, Anjali, Manoj, Bhavya, Nivedita, Jit, Glen, and Hardeep. Thank you so much for the laughter, high-fives, support, encouragement and many meals together. You made life much more bearable and joyful. Thank you so much, Soma Didi. You showed me the spiritual path to take during the most difficult period of my life. You are truly a life savior for me. Anupama Konara and Sanzida Jahan, you are the two sisters I never had. Both of you and your families have been with me in every happiness and sorrow. Without you, I would not have come this far. I am so lucky to be your best friend. Words are not enough to thank my parents (Ammi and Thaththi). Without your never-ending love, support and faith in me, I would not have come so far. My brother Chamara has always been a wonderful brother and great support. Thank you, Shamika akki for taking care of my family while I am far away from them. Last but not least, I am eternally grateful to my soul mate, Robby Zachariah. This thesis is a tribute to you because, without you, this thesis would not have been possible. You supported me as a lab member, my best friend, and my fiancé. Thank you so much for loving me endlessly, even when I am stubborn, crabby and cranky. You raised me up every time I fell and held me when I was depressed and so sick. I am so lucky to have you in my life. I cannot ever thank you enough for the everlasting love, inspiration, encouragement and faith. v Dedication “It is not the critic who counts; not the man who points out how the strong man stumbles, or where the doer of deeds could have done them better. The credit belongs to the man who is actually in the arena, whose face is marred by dust and sweat and blood; who strives valiantly; who errs, who comes short again and again, because, there is no effort without error and shortcoming; but who does actually strive to do the deeds; who knows great enthusiasms, the great devotions, who spends himself in a worthy cause; who at the best knows in the end triumph of high achievement, and who at the worst, if he fails, at least fails daring greatly, so that his place shall never be with those cold and timid souls who neither know victory nor defeat….” -Theodore Roosevelt- ‘Man in the Arena’ Speech April 23, 1910 Dedicated to my loving parents Mr.
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