Mono-methylation of lysine 27 at histone 3 confers lifelong susceptibility to stress.

Histone post-translational modifications are critical for mediating persistent alterations in gene expression. By combining unbiased proteomics profiling and genome-wide approaches, we uncovered a role for mono-methylation of lysine 27 at histone H3 (H3K27me1) in the enduring effects of stress. Specifically, mice susceptible to early life stress (ELS) or chronic social defeat stress (CSDS) displayed increased H3K27me1 enrichment in the nucleus accumbens (NAc), a key brain-reward region. Stress-induced H3K27me1 accumulation occurred at genes that control neuronal excitability and was mediated by the VEFS domain of SUZ12, a core subunit of the polycomb repressive complex-2, which controls H3K27 methylation patterns. Viral VEFS expression changed the transcriptional profile of the NAc, led to social, emotional, and cognitive abnormalities, and altered excitability and synaptic transmission of NAc D1-medium spiny neurons. Together, we describe a novel function of H3K27me1 in the brain and demonstrate its role as a "chromatin scar" that mediates lifelong stress susceptibility. [Display omitted] • Stress causes lifelong and cell-type-specific enrichment of H3K27me1 in nucleus accumbens • H3K27me1 accumulates across genes involved in neuronal excitability and neurotransmission • Expression of the VEFS domain of SUZ12 selectively induces H3K27me1 enrichment • VEFS expression induces behavioral and transcriptional signatures of stress susceptibility Torres-Berrío et al. establish a novel function of a form of histone methylation—H3K27me1—in the nucleus accumbens, part of the brain's reward circuitry, and demonstrate its role as a "chromatin scar" that mediates lifelong behavioral, physiological, and transcriptional signatures of stress susceptibility in mice. [ABSTRACT FROM AUTHOR]