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EPIGENETIC & TRANSCRIPTOMIC ALTERATIONS ASSOCIATED WITH CHILDHOOD MALTREATMENT, MAJOR DEPRESSIVE DISORDER, AND POST-TRAUMATIC STRESS DISORDER BY ANGELA CATHERINE BUSTAMANTE DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Neuroscience in the Graduate College of the University of Illinois at Urbana-Champaign, 2017 Urbana, Illinois Doctoral Committee: Associate Professor Monica Uddin, Chair Professor Karestan C. Koenen, Harvard University Associate Professor Alison M. Bell Professor Sandra Rodriguez-Zas ABSTRACT Childhood maltreatment increases the risk of developing major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) later in life. Dysregulation of the hypothalamic-pituitary- adrenal (HPA) axis, a regulator of the body’s stress response, has been associated with exposure to childhood maltreatment, MDD, and PTSD. Additional work has shown that a history of childhood maltreatment, MDD, and PTSD is associated with altered DNA methylation levels within key HPA axis genes. Despite this well-known association, the molecular mechanism(s) contributing to the increased risk of developing mental illness, specifically MDD or PTSD, following exposure to childhood maltreatment remain poorly understood. Therefore, the goal of my dissertation is to further elucidate the biologic mechanisms contributing to the relationship among childhood maltreatment, MDD, and PTSD by focusing on DNA methylation and gene expression. Chapter 2 investigates whether childhood maltreatment and MDD have a joint or potentially interacting effect on NR3C1, the glucocorticoid receptor, promoter region DNA methylation using whole blood. A secondary analysis examines the potential functional effect on downstream gene expression levels. Chapter 3 examines whether blood-derived DNA methylation of FKBP5, another HPA axis gene, mediates the relationship between childhood maltreatment and MDD, and whether DNA methylation subsequently influences FKBP5 gene expression. In Chapter 4, the genome-scale blood-based transcriptomic profiles of childhood maltreatment and PTSD are characterized and compared for overlap. Chapter 5 characterizes the genome-scale DNA methylation profiles associated with MDD in post-mortem brain. Results reveal that, despite clear evidence for a long-lasting biologic embedding of CM exposure, the subsequent impact of MDD and PTSD during adulthood is characterized by genomic signatures that are largely distinct from those associated with early life adversity. Taken together, these ii studies contribute to our current understanding of the biologic impact of childhood maltreatment, MDD, and PTSD on DNA methylation and gene expression levels. iii ACKNOWLEDGEMENTS First and foremost, I would like to acknowledge and thank my advisor and mentor, Dr. Monica Uddin, for her unending patience, guidance, and support throughout my graduate journey. I am grateful for all the encouragement, constructive criticism, and feedback she has given me, especially when it came to my writing! Monica has always been very receptive and open to my questions, random thoughts/ideas, and has always encouraged me to think independently and critically. She always challenged me to do my best, take on more responsibility, and to persevere despite minor setbacks and/or rejections. Under her guidance I have, without a doubt, become a better scientist and mentor. I am grateful to have had the opportunity to train in a supportive and intellectually stimulating environment. I would also like to thank my committee members, Dr. Alison Bell, Dr. Karestan Koenen, and Dr. Sandra Rodriguez-Zas for their support and advice. I am grateful for the insightful conversations and discussions we have shared over the course of this project. My lab mates, both current and former also deserve recognition for their support and invaluable friendship. Rich Soliven, Chao Zhang, and Levent Sipahi were some of the first people I met when I joined the lab in 2012 at Wayne State. They were always more than willing to offer advice, help troubleshoot, and even take a break to chat for a few minutes. I am thankful for the help and support they provided in the early stages of these projects. Here at Illinois, Grace Kim and John Pfeiffer have been great lab mates and friends. Both of you have made my last few years of grad school more enjoyable and I value our friendship. Don Armstrong, Carmen Valero, and Amy Weckle have always been honest, supportive, encouraging, and available to me whenever I had a question or just wanted to bounce an idea off of them. Lastly, I want to thank all of the additional friends I have made while in grad school both at Wayne State and Illinois. iv Especially, Will Gundling, Becky Androwski, Elizabeth Davis, Carly Drzewiecki, Stephen Fleming, Kevin Horecka, Francheska Morganti-Nieves, Lydia Nguyen, and Brett Velez I could not have asked for better friends to share this journey with. I would be remiss if I didn’t mention my family, who have been an integral part of my journey through grad school. My parents, Bill and Cathy, and siblings, Marje, Bill, Kate, and Jo, have provided endless love, support, and encouragement over the last 6 years. My parents instilled in me the dedication and work ethic that allowed me to persevere throughout my academic career and achieve my goals. They always encouraged me to pursue a career in a field I loved and, despite their reservations, supported my decision to pursue a Ph.D. My siblings have all been awesome role models and have each in their own way pushed me to do better in every aspect of my life. Despite the distance between the 5 of us, we have remained very close and involved in each other’s lives, even if two of them do not like the family group text. I am also very grateful for my in-laws, who have always been incredibly supportive and encouraging. Lastly, I would like to thank my husband Michael and daughter Evelyn. Mike, over the last (nearly) 11 years he has stood by my side and supported me through every endeavor and challenge I’ve faced. Mike has always encouraged me to consider all the options before making a decision, and did not hesitate to uproot our family when I said I wanted to finish my Ph.D. at Illinois. I cannot thank him enough for all the love, support, and tolerance (for my bizarre work hours) he has given me. I am particularly thankful for the slurpees after a rough day and how he can always get me to smile no matter how challenging and stressful the day was. Ev, has reminded me to enjoy and appreciate the little things, like bubbles and watching a windsock dance. She has made me happier than I ever thought possible and has pushed me to work even harder. Since the day Ev was born, she has provided me with a renewed sense of purpose and commitment in grad school. I am thankful for the level of excitement and extreme joy she v expresses just from seeing me at the end of the day, which will always be the best cure to any stressful day. vi TABLE OF CONTENTS CHAPTER 1: A GENERAL INTRODUCTION TO THE RELATIONSHIP BETWEEN EARLY LIFE ADVERSITY AND MENTAL ILLNESS ............................................................................... 1 CHAPTER 2: GLUCOCORTICOID RECEPTOR DNA METHYLATION, CHILDHOOD MALTREATMENT AND MAJOR DEPRESSION1 ......................................................................29 CHAPTER 3: FKBP5 DNA METHYLATION DOES NOT MEDIATE THE ASSOCIATION BETWEEN CHILDHOOD MALTREATMENT AND DEPRESSION SYMPTOM SEVERITY IN THE DETROIT NEIGHBORHOOD HEALTH STUDY2 ..............................................................55 CHAPTER 4: ALTERED TRANSCRIPTOMIIC PROFILES ASSOCIATED WITH CHILDHOOD MALTREATMENT AND POST-TRAUMATIC STRESS DISORDER .........................................78 CHAPTER 5: EPIGENETIC PROFILES ASSOCIATED WITH MAJOR DEPRESSIVE DISORDER IN THE HUMAN BRAIN ....................................................................................... 123 CHAPTER 6: GENERAL DISCUSSION ................................................................................. 149 REFERENCES ....................................................................................................................... 157 APPENDIX A: SUPPLEMENTAL TABLES .............................................................................. 187 vii CHAPTER 1: A GENERAL INTRODUCTION TO THE RELATIONSHIP BETWEEN EARLY LIFE ADVERSITY AND MENTAL ILLNESS ABSTRACT There is a well-documented link between exposure to early life adversity (ELA) and poor mental health later in life. More specifically, childhood maltreatment is known to increase the susceptibility to both major depressive disorder (MDD) and post-traumatic stress disorder (PTSD) during adulthood. Childhood maltreatment, or more broadly ELA, MDD, and PTSD, have all been associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, a key regulator of the body’s stress response. Despite the established link between ELA and increased susceptibility to MDD and PTSD, the molecular mechanisms contributing to this relationship are poorly understood. In order to gain a deeper understanding of this relationship and the biologic mechanisms contributing to it, we must first understand the impact of each exposure on different biologic systems and processes. The biologic systems and processes that will be reviewed include: the HPA axis, stress-related mental disorders, dysregulation of the HPA axis, epigenetics as a potential mediator of mental illness, and gene expression. Despite the observable association
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