Epigenetic Priming of H3K4 in the Brain: Inducing a Hyperactive Response To Stress in Mice & Site-Specific Epigenetic Editing with CRISPR

Abstract

The emerging field of epigenetics posits that one way we adapt and interact with our environment is through epigenetic changes: changes in transcriptional state or potential transcriptional activity that do not change genes themselves. Previous research has established a link between trauma in early life with an overactive stress response and increased vulnerability to psychiatric disease, possibly mediated by epigenetic mechanisms. However, there remains a gap in our understanding of the cellular mechanisms that link early life trauma with an overactive stress response and increased vulnerability to psychiatric illnesses. The goal of this senior thesis is to build a better understanding of epigenetic priming during development as a cellular mechanism by which the brain is more sensitive to environmental experiences. In this thesis we used viral-mediated epigenetic modifications and behavioral testing to demonstrate that widespread epigenetic modifications in the developing mouse nucleus accumbens (NAc) with histone methyltransferase Setd7 is sufficient to prime the brain and cause a hyperactive response to stress in adulthood. Next, we tested the ability of a new epigenome editing tool using CRISPR and Setd7 to prime specific enhancer regions of the C-fos gene to validate site-specific priming that results in selective overexpression upon further activation.