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MECHANISTIC INSIGHTS INTO CHROMATIN MEDIATED GENE REGULATION IN ROTENONE-INDUCED NEURODEGENERATION. by Dana M. Freeman A dissertation submitted to Johns Hopkins University in conformity with the requirements for the degree of Doctor of Philosophy Baltimore, Maryland April 2020 Abstract Rotenone is an organic pesticide and non-selective piscicide that is approved for use in the United States (US). In human epidemiological studies, rotenone exposure increases the risk of Parkinson’s disease (PD), the second most common neurodegenerative disorder in the US. Rotenone is a key toxicant used to study gene- environment interactions in neuronal function and aging. In experimental studies, rotenone exposure recapitulates PD cellular pathology at environmentally relevant concentrations. It is a potent complex I inhibitor and promotes the production of reactive oxygen species. Oxidative damage and mitochondrial dysfunction activate critical transcription factors that regulate the cellular stress response. This retrograde signaling pathway alters chromatin structure via epigenetic mechanisms to regulate gene expression. Epigenetic modifications including DNA methylation and histone tail acetylation are persistent and can have a lasting effect on the functionality of a neuron. Investigating the mechanisms and patterning of these epigenetic modifications is critical for understanding the role of the epigenome in maintaining neuronal plasticity during aging. In this dissertation, we examined the molecular signatures of rotenone exposure on the epigenome. We investigated the role of the endogenous protein α-Synuclein (α- Syn), a pathological hallmark of PD, in mediating the effects on chromatin. We discovered that oxidative stress-induced α-Syn interferes with the maintenance of DNA methylation patterns by interfering with the translocation of DNA methyltransferase I. The aggregation of α-Syn activates ATF4 signaling and represses the hypoxic response. We revealed that enhancer enriched PD-associated genetic variants, DNMT1-dependent regions, hypoxia-response elements, and CTCF transcription factor binding motifs were among the genomic elements most vulnerable to rotenone-induced oxidative damage and α-Syn toxicity. We hypothesize that mitochondrial dysfunction activates early ii response transcription factors to regulate the balance and activity of DNA modifying enzymes in the nucleus and that α-Syn toxicity drives the direction of this response. There is currently no cure for PD and clinical strategies rely on treating symptoms that occur late after onset of pathology. Epigenetic modifications are persistent, but they are also reversible. This dissertation provides insights into molecular signatures of oxidative stress in the brain and introduces candidate regions for early biological markers and novel pharmaceutical targets. Advisor: Zhibin Wang, Associate Professor Department of Environmental Health & Engineering Bloomberg School of Public Health Thesis Committee Chair: Robert Casero, Professor Department of Oncology Sidney Kimmel Comprehensive Cancer Center Thesis Committee Members: John Groopman, Professor: Department of Environmental Health & Engineering Jiou Wang, Associate Professor: Department of Biochemistry & Molecular Biology James Yager, Professor Emeritus: Department of Environmental Health & Engineering Thomas Hartung, Professor: Department of Environmental Health & Engineering Wan-yee Tang, Professor: Department of Environmental Health & Engineering iii Preface I’ve always loved to learn. When I was younger, my parents made learning an everyday part of our lives. Whether it was a vacation to a historic monument or a fun memorization game on long car rides, my parents always encouraged me to be curious. I’m fortunate to have grown up in an environment where I could be anything I wanted if I worked hard enough and my ethnicity, social class, religion, or sex would not hinder me from that. That privilege I not only recognize but promise to take advantage of for the sake of people less fortunate than me as I move forward with my life and my career. I’d like to dedicate this dissertation to my mother and father for all their sacrifices, love, and support. When I entered college in 2009, next generation sequencing was at the forefront of the new age of Biology. Almost a decade after the first draft of the human genome was published, I was convinced I would study how our genetic code would cause disease. I started working for Dr. Raquel Lieberman under the supervision of Dr. Rebecca Donegan at Georgia Tech. This experience changed my life. Not only did it give me a passion for research, it gave me the desire to answer a prominent question in the field at that time. Why do we still struggle to comprehend the etiology of most diseases if we know the genetic code and its variation in the human population? After college, I went to the National Center for Environmental Health. I’m grateful for all the wonderful people I met at the Centers for Disease Control and the freedom I was given to explore the vast world of Public Health. It was here that I learned about the idea of gene-environment interactions. My favorite quote by George Gray describing this phenomenon is “Genetics loads the gun; the environment pulls the trigger.” I came to Johns Hopkins Bloomberg School of Public Health in August 2015. I am grateful that I began my journey with Lena Smirnova, Georgina Harris, and the Center for Alternatives to Animal Testing. They welcomed me into the department with open arms and taught me invaluable lessons in cell culture technique. Through the help of my cohort, my friends, my lab mates, and mentors; I was able to develop a project that tied together all my interests. I was elated to start working on gene-environment interactions in the brain and understanding the molecular mechanisms involved in exposure driven neurological disorders. I’d like to thank the department for providing me with this amazing opportunity and the NIEHS and NHLBI T32 training grant for funding my education. I’d also like to thank the Frederik Bang Award and the Environmental Health & Engineering Chen Award for believing in my work and providing the funding for me to accomplish this goal. I want to thank all my friends for their unwavering support. The Lady Scholars Club for keeping me grounded and never allowing me to give up on myself. My friends back home who have over the years become the best family I could ever imagine. Thank you for always reminding me who I am and where I’ve come from. My dog, Blazer, for always knowing when I need to take a walk break or a nap. He also spent countless evenings with me on the couch while writing. Last, but certainly not least, thank you to my best friend and partner in life Zack Ballew. We’ve come a long way from being those crazy kids at Tech but you still make me feel connected to that person in all the best ways. I would never have come this far without you. I love you 2 ∞ & →. iv Table of Contents Abstract ............................................................................................................................... ii Preface ............................................................................................................................... iv Table of Contents .............................................................................................................. v Table of Tables ............................................................................................................... viii Table of Figures ................................................................................................................. x CHAPTER 1 ......................................................................................................... 2 1.1 SIGNIFICANCE .......................................................................................................... 2 1.1.1 PESTICIDE USAGE IN THE US .............................................................................. 2 1.1.2 EPIDEMIOLOGICAL EVIDENCE OF ROTENONE IN NEURODEGENERATION .................. 3 1.1.3 PARKINSON’S DISEASE IN THE US ........................................................................ 4 1.2 BACKGROUND ......................................................................................................... 5 1.2.1 CLINICAL AND MOLECULAR FEATURES OF PARKINSON’S DISEASE .......................... 5 1.2.2 ENVIRONMENTAL PARKINSON’S DISEASE ............................................................. 7 1.2.3 ROTENONE INDUCED MODELS OF PARKINSON’S DISEASE ..................................... 8 1.2.4 EPIGENETIC MECHANISMS MEDIATE GENE-ENVIRONMENT INTERACTIONS ............ 10 1.2.5 EPIGENETIC INSIGHTS IN PARKINSON’S DISEASE ................................................ 11 1.2.6 EPIGENETIC MODIFICATIONS IN ROTENONE INDUCED PARKINSON’S DISEASE ........ 14 1.3 OVERVIEW OF SPECIFIC AIMS .................................................................................. 15 1.4 INNOVATION AND IMPACT ........................................................................................ 16 1.5 REFERENCES ......................................................................................................... 18 CHAPTER 2 ....................................................................................................... 25 PART A. ROTENONE REGULATES LEVELS OF 5MC & H3K27AC .................................... 26 2.2 INTRODUCTION .....................................................................................................
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