Promoting Resilience to Early Life Stress through Epigenetic Editing

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PROJECT SUMMARY / ABSTRACT Early life stress (ELS) is one of the strongest predictors for development of mood and anxiety disorders. ELS can include trauma (neglect, and/or physical, sexual, and/or emotional abuse) or other negative childhood experiences. However, the increased risk for depression following ELS is not well understood. Previous work in a mouse model of stress across the lifespan has shown unique gene expression patterns after ELS and adult stress in the nucleus accumbens (NAc), a key region of the reward pathway implicated in stress response. The three-dimensional structure of chromatin is a key factor in determining how genes are regulated and expressed, with more open and accessible chromatin being permissive for gene expression and more closed chromatin repressing expression. We hypothesize that ELS changes chromatin accessibility within stress-responsive neuronal cells in the NAc such that the chromatin adopts a comparatively open conformation, making transcription more reactive to future stimuli. In Aim 1, I will determine how chromatin architecture is altered specifically within ELS-activated neurons using a double-transgenic mouse to label and capture both activated and non-activated neurons, then perform ATAC-sequencing and computational analyses to determine chromatin accessibility across the entire genome. I will examine how ELS alters chromatin structure in activated and non-activated cells in juvenile and adult mice of both sexes. In Aim 2, I will test the functional impact of chromatin state on transcriptional and behavioral susceptibility to adulthood stressors. First, I will apply CRISPR-dCas9-based epigenome editing tools to close chromatin at target genomic enhancer regions already identified in preliminary data to prevent hypersensitivity to activation in vitro. Then, I will use this tool in vivo to test the hypothesis that closing aberrantly open chromatin can reverse the impact of ELS and promote transcriptional and behavioral resilience. Together, this research will generate fundamental insights into how stress during key periods of development increases sensitivity to future stress at a molecular level in the brain.This project contributes to our understanding of the epigenetic mechanisms driving heightened risk of mood disorders following ELS.