Epigenetic & transcriptomic alterations associated with childhood maltreatment, major depressive disorder, and post-traumatic stress disorder

Epigenetics;Gene expression;Childhood maltreatment;Major depressive disorder;Post-traumatic stress disorder

Bustamante, Angela Catherine

关键词: Epigenetics;    Gene expression;    Childhood maltreatment;    Major depressive disorder;    Post-traumatic stress disorder;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/98124/BUSTAMANTE-DISSERTATION-2017.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

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 studies contribute to our current understanding of the biologic impact of childhood maltreatment, MDD, and PTSD on DNA methylation and gene expression levels.