An Analysis of Chromatin Profiles in Early Life Stress Responsive Cells in the Nucleus Accumbens

Abstract

Early life stress (ELS) is a term which is used to describe a variety of forms of childhood adversity, including forced displacement, poverty, and neglect. Research involving both human and rodent subjects has shown that individuals who experience ELS are at higher risk of developing psychiatric disorders following a second experience (or, “hit”) of stress in adulthood. Studies with rodent models have allowed for the discovery that this sensitization to stress is accompanied by unique transcriptional patterns. These behavioural and transcriptional results together suggest that epigenetic mechanisms may play a role in the sensitization of stress following ELS. We hypothesized that epigenetic mechanisms may prime chromatin to adopt an open but not active state after an experience of early life stress, and that these regions of chromatin may become active following additional future stress. To investigate this question, we used ATAC-seq to analyze chromatin accessibility in adult mice that had experienced ELS. We specifically focused on the nucleus accumbens (NAc) as it is a key player in reward processing and has been shown to have alterations in the transcriptional activity of its cells following ELS. We also compared the chromatin accessibility data from this experiment with earlier discoveries in NAc cells from juvenile mice that underwent ELS. My analysis found that ELS induces chromatin to adopt a more accessible conformation into adulthood, primarily at intergenic regions. This is especially exciting as intergenic regions contain enhancer elements which regulate transcription. This result suggests that an enhancer priming mechanism may underlie the unique transcriptional patterns observed following two-hits of stress. Moreover, further analysis reveals that most of our changes to chromatin accessibility occur in or around genes relevant for psychiatric development, further suggesting that chromatin regulation following ELS may underlie increased susceptibility to psychiatric illness.