EARLY-LIFE STRESS ALTERS POSTNATAL CHROMATIN ARCHITECTURE AND DEVELOPMENT IN A BRAIN REWARD REGION

Abstract

This thesis presents work investigating how early-life stress (ELS) affects chromatin architecture and development. ELS sensitizes individuals to subsequent stressors, which increases lifetime risk for psychiatric disorders. ELS includes negative experiences such as abuse, neglect, loss of a caregiver, and survival of traumatic events such as exposure to violence or natural disaster. ELS impacts cellular and transcriptomic response to additional stress within the brain’s reward circuitry. How early experiences encode such long-lasting effects is poorly understood but implicates the epigenetic response process, particularly at the level of long-lasting global chromatin architecture remodeling. Here, I describe how epigenetic memory processes could be influenced by ELS, present empirical work showing how chromatin architecture and development change after ELS, and briefly explore potential methods for determining the role individual chromatin regions may play in the ELS susceptibility phenomenon.The empirical work focuses on the effect of ELS on the nucleus accumbens (NAc) — a key limbic brain region, with some discussion of other regions implicated in the reward pathway. Using leading-edge techniques, we find that early-life stress initially opens chromatin in stress-activated cells, suggesting epigenetic priming as a mechanism of stress sensitization. By adulthood, we observe chromatin remodeling throughout the NAc, indicating that the effects of stress are long-lasting and propagate across development into the broader cell population. We also find that deposition of H3K4me1 in NAc during early postnatal development is sufficient to mimic early-life stress and prime hypersensitivity to subsequent stress. We conclude that a molecular memory of early-life stress is encoded at an epigenetic level through changes in chromatin architecture. To complement the initial genome-wide manipulation studies, I have set the groundwork to target specific genomic loci for epigenetic suppression or priming by CRISPR dSaCas9-mediated epigenetic editing, in vitro. This approach was designed to utilize dSaCas9-effector complexes to target enhancers and other regulatory elements to impact chromatin architecture or gene expression, ultimately giving rise to resilience or susceptibility to future stress. While additional work is needed to optimize these systems, this approach has the potential to functionally test whether suppressing or priming specific genomic enhancers during development can promote resilience or sensitivity, respectively, to later stress. Together, this work generates fundamental insights into how stress during key developmental periods increases sensitivity to future stress at an epigenetic level in the brain.