吗啡通过多梳抑制复合物 2（PRC2）在 mESCs 中的自我调节机制导致 H3K27me3 水平的全基因组变化。

Morphine leads to global genome changes in H3K27me3 levels via a Polycomb Repressive Complex 2 (PRC2) self-regulatory mechanism in mESCs.

机构信息

Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), 48940, Leioa, Bizkaia, Spain.

Innovation in Assisted Reproduction Group, Bizkaia Health Research Institute, 48903 Barakaldo, Bizkaia, Spain.

出版信息

Clin Epigenetics. 2020 Nov 9;12(1):170. doi: 10.1186/s13148-020-00955-w.

DOI:10.1186/s13148-020-00955-w

PMID:33168052

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7654014/

Abstract

BACKGROUND

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.

RESULTS

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.

CONCLUSIONS

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.

摘要

背景

环境诱导的表观遗传变化可导致健康问题或疾病，但其中涉及的机制仍不清楚。吗啡可穿过胎盘屏障，导致胚胎发育异常。然而，吗啡引起这些效应的机制以及它们有时如何持续到成年期尚不清楚。为了解开吗啡引起的染色质改变在胚胎发育异常中的作用，我们探讨了 H3K27me3/PRC2 抑制复合物在基因表达中的作用及其在细胞世代中的传递，以响应吗啡。

结果

我们使用小鼠胚胎干细胞作为模型系统，发现慢性吗啡处理诱导组蛋白修饰 H3K27me3 的全局下调。相反，ChIP-Seq 显示在特定基因组位点，特别是启动子处，H3K27me3 水平显著增加，破坏了与胚胎发育、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高 H3K27me3 水平，下调负责 H3K27me3 的 PRC2 成分的转录。吗啡去除后，PRC2 成分的下调至少持续 48 小时（4 个细胞周期），尽管启动子 H3K27me3 水平恢复到对照水平。

结论

吗啡诱导 PRC2 复合物靶向选定的启动子，包括 PRC2 成分的启动子，导致基因表达的特征变化和 H3K27me3 的全局减少。在去除吗啡后，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。我们认为 H3K27me3 参与启动吗啡诱导的基因表达变化，但不参与其维持。多梳抑制复合物 2 (PRC2) 和慢性吗啡暴露诱导的 H3K27me3 改变的模型。吗啡诱导 H3K27me3 在编码 PRC2 复合物核心成员的基因启动子处富集，并与它们的转录下调相关。