Max Planck Institute of Psychiatry, Munich, Germany.
Stress. 2011 Nov;14(6):581-9. doi: 10.3109/10253890.2011.602146. Epub 2011 Aug 19.
Stress during early life can impact the developing brain and increase vulnerability to mood disorders later in life. Here, we argue that epigenetic mechanisms can mediate the gene-environment dialogue in early life and give rise to persistent epigenetic programming of adult physiology eventually resulting in disease. Early life stress in mice leads to epigenetic marking of the arginine vasopressin (AVP) gene underpinning sustained expression and increased hypothalamic-pituitary-adrenal axis activity. This epigenetic memory is laid down in the parvocellular neurons of the paraventricular nucleus and involves Ca(2+)/calmodulin kinase-mediated phosphorylation of the methyl-CpG binding domain protein MeCP2 leading to dissociation from its DNA-binding site and derepression of the AVP gene. The reduced occupancy of MeCP2 during this early stage of life facilitates the development of hypomethylation at the AVP enhancer, which sustains derepression throughout later life and thereby serves to hardwire early life experiences. The sequential order of these events may represent a critical time window for the preventive therapy of severe trauma.
早期生活中的压力会影响大脑发育，并增加日后患情绪障碍的脆弱性。在这里，我们认为，表观遗传机制可以调节早期生活中的基因-环境对话，并导致成年生理的持久表观遗传编程，最终导致疾病。在老鼠身上的早期生活压力会导致精氨酸加压素（AVP）基因的表观遗传标记，从而支撑持续表达和增加下丘脑-垂体-肾上腺轴的活动。这种表观遗传记忆被刻在室旁核的小细胞神经元中，涉及钙/钙调蛋白激酶介导的甲基-CpG 结合域蛋白 MeCP2 的磷酸化，导致其与 DNA 结合位点分离，并使 AVP 基因去抑制。在生命的早期阶段，MeCP2 的占有率降低，促进了 AVP 增强子的低甲基化，这种低甲基化在以后的生活中持续存在，从而为早期生活经历提供了固定的模式。这些事件的顺序可能代表了严重创伤预防性治疗的关键窗口期。
