Genome-wide DNA methylation investigation of stress

Abstract

iii ACKNOWLEDGEMENTS I have been fortunate to have the support and contributions of many individuals that has enabled the culmination of this body of work. My mentor, Jimmy Potash, has provided perceptive guidance throughout my graduate career in our discussions of the myriad aspects of research, science, and life. Benjamin Hing helped both tangibly in my mastery of laboratory techniques and intangibly as I grew into an independent researcher. Much of this research was possible by the instigation and oversight of Gen Shinozaki whose innovative ideas helped shape my investigations. I would like to thank my thesis committee members for their constructive advice. Past and current members of the Potash and Shinozaki labs aided in many fundamental aspects of my research, and without the key collaborations with individuals of the Departments of Oral and Maxillofacial Surgery and Neurosurgery, this research would not have been possible.My steps in the program were greatly facilitated by the director, administrators, and members of the Interdisciplinary Graduate Program in Genetics.Although my love of science began early, my path had many twists and turns, and certain people have been instrumental in my journey. This includes my high school teacher Barbara Lipnick, who strengthened my love of learning, and my college professor Ellen DuPre, who spurred me into the research path. Lastly, I would like to express my appreciation for my family and friends for their continuous support. My sister, Emily, has been a sounding board for any problem, small or large, and my mother, brothers, and sisters-in-law have been the best advocates in all my endeavors.iv ABSTRACT Stress contributes to the development of major depressive disorder (MDD) and posttraumatic stress disorder (PTSD), and an intermediary factor between stress and psychiatric disorders may be epigenetics. Studies have shown altered DNA methylation (DNAm) in animal models of and humans with stress exposure and in individuals with PTSD and MDD. The availability of genome-wide experimental platforms has given us new tools to investigate DNAm, and in this dissertation these techniques have been used to further our current understanding of the epigenetics of stress.We performed a genome-wide investigation in mice exposed to chronic stress that exhibit depressive-and anxious-like behaviors, examining DNAm changes within the dentate gyrus, a sub-region of the hippocampus that contributes to the stress response. Using the Methyl-Seq method, an intergenic region of chromosome X was shown to be differentially methylated with chronic stress, and this finding replicated in two additional cohorts of mice. In postmortem brain tissue of humans with MDD, an increase in DNAm within this intergenic region was also found.Animal models do not fully capture the complexity of stress and psychiatric disorders in humans, but comparable studies in humans are limited by the difficulty of obtaining brain tissues. Instead, these studies have used peripheral tissues to examine DNAm changes related...