Research Laboratory of Psychobiology, Department of Psychiatry, Rambam Medical Center, Bruce Rappaport Faculty of Medicine, Technion IIT, Haifa, Israel.
Int J Neuropsychopharmacol. 2010 Apr;13(3):347-59. doi: 10.1017/S146114570999071X. Epub 2009 Oct 1.
Post-traumatic stress disorder (PTSD) is unique among psychiatric disorders since there is an explicit requirement for the presence of a well-defined precipitating environmental event. This suggests the participation of adaptable molecular processes such as epigenetic modifications, including acetylation and methylation of histones and DNA methylation. In the present study we investigated whether changes in DNA methylation are associated with the effects of traumatic stressor, using a validated PTSD rat model. Screening of genomic DNA methylation patterns revealed that maladaptation to traumatic stress is associated with numerous changes in the methylation pattern of rat hippocampus. Of the differentially methylated genes revealed by this global screening, Disks Large-Associated Protein (Dlgap2) was of special interest, demonstrating an increase in a specific methylation site which was associated with a reduction in its gene expression in PTSD-like compared to non-PTSD-like rats. The association between the methylation rate and Dlgap2 expression was further substantiated by re-dividing the rats according to their methylation state. A significantly higher expression was observed in the non-methylated compared to methylated rats. In addition, taking all rats as one group revealed a significant correlation between their behavioural stress responses and Dlgap2 transcript levels. These results suggest that alterations in global methylation pattern are involved in behavioural adaptation to environmental stress and pinpoint Dlgap2 as a possible target in PTSD.
创伤后应激障碍（PTSD）在精神障碍中是独特的，因为它明确要求存在明确界定的诱发环境事件。这表明适应性分子过程的参与，如表观遗传修饰，包括组蛋白的乙酰化和甲基化以及 DNA 甲基化。在本研究中，我们使用经过验证的 PTSD 大鼠模型研究了 DNA 甲基化的变化是否与创伤性应激的影响有关。基因组 DNA 甲基化模式的筛选表明，适应不良与创伤性应激相关，与大鼠海马体的甲基化模式的许多变化有关。通过这种全面筛选揭示的差异甲基化基因中，Disk 大相关蛋白（Dlgap2）特别引人注目，其在 PTSD 样大鼠与非 PTSD 样大鼠相比，特定甲基化位点的增加与基因表达的减少有关。这种甲基化率与 Dlgap2 表达之间的关联通过根据甲基化状态重新划分大鼠进一步得到证实。未甲基化大鼠的表达明显高于甲基化大鼠。此外，将所有大鼠作为一组进行分析，发现它们的行为应激反应与 Dlgap2 转录水平之间存在显著相关性。这些结果表明，全基因组甲基化模式的改变参与了对环境应激的行为适应，并将 Dlgap2 确定为 PTSD 的一个可能靶点。
