Early-life stress alters H3K4me1 in VTA to prime stress sensitivity

Early-life stress increases gene expression, neurophysiological, and behavioral responses to subsequent stress. Here, we determined the role of chromatin in such long-lasting sensitivity. We used a combination of bottom-up mass spectrometry, viral-mediated epigenome editing, RNA sequencing, patch-clamp electrophysiology of dopamine neurons, and behavioral quantification in a mouse model of early-life stress, focusing on the ventral tegmental area (VTA), a key dopaminergic brain region. We found that early-life stress enriches histone-3 lysine-4 monomethylation-associated with open chromatin and primed or active enhancers-and the H3K4 monomethylase SETD7. Mimicking early-life stress through postnatal overexpression of Setd7 and enrichment of H3K4me1 in the VTA sensitizes transcriptional, physiological, and behavioral responses to adult stress, while Setd7 knockdown ameliorates the impact of early-life stress. These findings link early-life stress experience to long-term stress hypersensitivity within the brain's dopaminergic circuitry, providing a mechanism by which early-life stress increases risk for mood and anxiety disorders later in life.