Environmentally induced epigenetic changes can lead to health problems or disease, but the mechanisms involved remain unclear. Morphine can pass through the placental barrier leading to abnormal embryo development. However, the mechanism by which morphine causes these effects and how they sometimes persist into adulthood is not well known. To unravel the morphine-induced chromatin alterations involved in aberrant embryo development, we explored the role of the H3K27me3/PRC2 repressive complex in gene expression and its transmission across cellular generations in response to morphine. Using mouse embryonic stem cells as a model system, we found that chronic morphine treatment induces a global downregulation of the histone modification H3K27me3. Conversely, ChIP-Seq showed a remarkable increase in H3K27me3 levels at specific genomic sites, particularly promoters, disrupting selective target genes related to embryo development, cell cycle and metabolism. Through a self-regulatory mechanism, morphine downregulated the transcription of PRC2 components responsible for H3K27me3 by enriching high H3K27me3 levels at the promoter region. Downregulation of PRC2 components persisted for at least 48 h (4 cell cycles) following morphine removal, though promoter H3K27me3 levels returned to control levels. Morphine induces targeting of the PRC2 complex to selected promoters, including those of PRC2 components, leading to characteristic changes in gene expression and a global reduction in H3K27me3. Following morphine removal, enhanced promoter H3K27me3 levels revert to normal sooner than global H3K27me3 or PRC2 component transcript levels. We suggest that H3K27me3 is involved in initiating morphine-induced changes in gene expression, but not in their maintenance. Model of Polycomb repressive complex 2 (PRC2) and H3K27me3 alterations induced by chronic morphine exposure. Morphine induces H3K27me3 enrichment at promoters of genes encoding core members of the PRC2 complex and is associated with their transcriptional downregulation.

中文翻译：

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吗啡通过 mESC 中的多梳抑制复合物 2 (PRC2) 自我调节机制导致 H3K27me3 水平的全球基因组变化

环境诱导的表观遗传变化会导致健康问题或疾病，但所涉及的机制尚不清楚。吗啡可以穿过胎盘屏障，导致胚胎发育异常。然而，吗啡导致这些影响的机制以及它们有时如何持续到成年尚不清楚。为了解开吗啡诱导的异常胚胎发育中涉及的染色质改变，我们探索了 H3K27me3/PRC2 抑制复合物在基因表达中的作用及其跨细胞世代的传递以响应吗啡。使用小鼠胚胎干细胞作为模型系统，我们发现慢性吗啡治疗会诱导组蛋白修饰 H3K27me3 的全局下调。相反，ChIP-Seq 显示特定基因组位点的 H3K27me3 水平显着增加，特别是启动子，破坏与胚胎发育、细胞周期和代谢相关的选择性靶基因。通过自我调节机制，吗啡通过在启动子区域富集 H3K27me3 的高水平来下调负责 H3K27me3 的 PRC2 成分的转录。去除吗啡后，PRC2 组分的下调持续至少 48 小时（4 个细胞周期），尽管启动子 H3K27me3 水平恢复到控制水平。吗啡诱导PRC2 复合物靶向选定的启动子，包括PRC2 组件的启动子，导致基因表达的特征性变化和H3K27me3 的整体减少。去除吗啡后，增强的启动子 H3K27me3 水平比全局 H3K27me3 或 PRC2 成分转录水平更早恢复正常。我们建议 H3K27me3 参与启动吗啡诱导的基因表达变化，但不参与其维持。慢性吗啡暴露诱导的 Polycomb 抑制复合物 2 (PRC2) 和 H3K27me3 改变模型。吗啡在编码 PRC2 复合体核心成员的基因的启动子上诱导 H3K27me3 富集，并与它们的转录下调有关。