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.

中文翻译：

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组蛋白 3 上赖氨酸 27 的单甲基化赋予终生对压力的敏感性


组蛋白翻译后修饰对于介导基因表达的持续改变至关重要。通过结合公正的蛋白质组学分析和全基因组方法，我们发现了组蛋白 H3 (H3K27me1) 赖氨酸 27 单甲基化在应激持久影响中的作用。具体来说，易受早期生活压力 (ELS) 或慢性社交失败压力 (CSDS) 影响的小鼠在伏隔核 (NAc)（大脑的关键奖励区域）中表现出 H3K27me1 富集增加。应激诱导的 H3K27me1 积累发生在控制神经元兴奋性的基因上，并由 SUZ12 的 VEFS 结构域介导，SUZ12 是多梳抑制复合物 2 的核心亚基，控制 H3K27 甲基化模式。病毒 VEFS 表达改变了 NAc 的转录谱，导致社交、情绪和认知异常，并改变了 NAc D1 中棘神经元的兴奋性和突触传递。我们共同描述了 H3K27me1 在大脑中的一种新功能，并证明了它作为介导终生压力敏感性的“染色质疤痕”的作用。