National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China.
National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy/Collaborative Innovation Center for Biotherapy, West China Hospital of Sichuan University, Chengdu 610041, China; Shenzhen Key Laboratory of Drug Addiction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
Genomics Proteomics Bioinformatics. 2023 Jun;21(3):551-572. doi: 10.1016/j.gpb.2023.03.003. Epub 2023 May 19.
The expression of linear DNA sequence is precisely regulated by the three-dimensional (3D) architecture of chromatin. Morphine-induced aberrant gene networks of neurons have been extensively investigated; however, how morphine impacts the 3D genomic architecture of neurons is still unknown. Here, we applied digestion-ligation-only high-throughput chromosome conformation capture (DLO Hi-C) technology to investigate the effects of morphine on the 3D chromatin architecture of primate cortical neurons. After receiving continuous morphine administration for 90 days on rhesus monkeys, we discovered that morphine re-arranged chromosome territories, with a total of 391 segmented compartments being switched. Morphine altered over half of the detected topologically associated domains (TADs), most of which exhibited a variety of shifts, followed by separating and fusing types. Analysis of the looping events at kilobase-scale resolution revealed that morphine increased not only the number but also the length of differential loops. Moreover, all identified differentially expressed genes from the RNA sequencing data were mapped to the specific TAD boundaries or differential loops, and were further validated for changed expression. Collectively, an altered 3D genomic architecture of cortical neurons may regulate the gene networks associated with morphine effects. Our finding provides critical hubs connecting chromosome spatial organization and gene networks associated with the morphine effects in humans.
线性 DNA 序列的表达受染色质的三维（3D）结构精确调控。吗啡诱导的神经元异常基因网络已被广泛研究；然而，吗啡如何影响神经元的 3D 基因组结构仍不清楚。在这里，我们应用仅消化-连接高通量染色体构象捕获（DLO Hi-C）技术来研究吗啡对灵长类皮质神经元 3D 染色质结构的影响。在恒河猴上连续接受吗啡给药 90 天后，我们发现吗啡重新排列了染色体区域，总共切换了 391 个分段隔室。吗啡改变了超过一半检测到的拓扑关联域（TAD），其中大多数表现出各种移位，其次是分离和融合类型。在千碱基分辨率下对环化事件的分析表明，吗啡不仅增加了差异环的数量，而且增加了差异环的长度。此外，从 RNA 测序数据中鉴定出的所有差异表达基因都映射到特定的 TAD 边界或差异环上，并进一步验证了表达变化。总之，皮质神经元的 3D 基因组结构的改变可能调节与吗啡作用相关的基因网络。我们的发现为连接人类染色体空间组织和与吗啡作用相关的基因网络提供了关键枢纽。
