Epigenetic priming of response to future stressors

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PROJECT SUMMARY Early life adversity (ELA) is one of the strongest lifetime risk factors for depression, anxiety, suicide, and other psychiatric disorders, particularly after facing additional stressful events later in life. ELA sensitizes individuals to future stressors and doubles the likelihood that a stressor in adulthood will result in an episode of depression or anxiety. However, the neurobiological basis of this stress sensitivity, or priming, remains almost entirely unexplored. Clinical and preclinical studies demonstrate a role for the ventral tegmental area (VTA) in ELA- attributable mood and anxiety disorders, and that ELA alters the course of VTA development and its function in response to both stressors and rewards. Using a mouse model to investigate the neurobiological impact of ELA, I previously found that ELA leads to lifelong transcriptomic changes in VTA including unique transcriptional response to adult stressors, which parallels latent behavioral changes we have observed. Gene expression is regulated by epigenetic mechanisms, and it was recently shown that the chromatin landscape continues to mature postnatally during a time when ELA has the greatest impact on stress sensitivity. Chromatin dynamically responds to developmental and environmental cues, acts as a substrate of molecular memory in cells, and facilitates adaptive gene expression response to recurring stimuli, a phenomenon termed epigenetic priming. In this Biobehavioral Research Awards for Innovative New Scientists (BRAINS) proposal, I will test the conceptually innovative hypothesis that ELA alters maturation of the chromatin landscape, priming chromatin in a cell-type- specific manner as a biological mechanism of heightened reactivity to future stimuli. In Aim 1 we will apply cutting- edge sequencing approaches and computational analyses to understand how the chromatin landscape matures across normal postnatal development with cellular specificity, how ELA alters these trajectories, and whether such changes are engaged in enhanced response to future stressors. In Aim 2 we will develop novel epigenome editing tools to prime targeted genomic locations, which we will test in vitro and apply in vivo to understand mechanisms of sensitivity to future stimuli. While our CRISPR/dCas9-based epigenome priming approach entails a degree of risky innovation, it is balanced by promising preliminary data and we provide alternative approaches that would mitigate failure of this high-risk high-reward experiment. The proposed research will identify the neuroepigenetic mechanisms through which developmental brain plasticity encodes adversity and confers sensitivity to future stressors. This proposal is directly relevant to the NIMH Strategic Goal to examine mental illness trajectories across the lifespan. Understanding how ELA alters the course of brain development at the level of the epigenome has the potential to transform our understanding of the neurodevelopmental origins of ELA-attributable mental illness and potential critical windows for intervention. The Advisory Council formed through this BRAINS Award will optimally support the ultimate goal of translating our findings into development of novel treatments to mitigate the impact of childhood adversity on adverse mental health outcomes.