Max Planck Institute of Psychiatry.
Epigenetics. 2010 Apr;5(3):194-9. doi: 10.4161/epi.5.3.11375. Epub 2010 Apr 1.
Early-life stress induces persistent memory traces on our genes and programs the life-long risk for depression. Epigenetic marking of the arginine vasopressin (AVP) gene by early-life stress in mice underpins sustained expression and increased hypothalamic-pituitary-adrenal axis activity, triggering endocrine and behavioral alterations that are frequent features in depression. This epigenetic memory evolves in two steps coordinated by the epigenetic reader and writer MeCP2. While early derepression of AVP is driven by neuronal activity causing Ca2+/calmodulin kinase-dependent phosphorylation and dissociation of MeCP2, subsequent hypomethylation at the AVP enhancer gradually develops to sustain derepression. In a vicious circle MeCP2 occupancy uncouples from the initial stimulus and leads to the hard-coding of early-life experience at the level of DNA methylation. The sequential order of these events demarcates the transition from a preliminary to a persistent, possibly irreversible, epigenetic memory and thus defines a critical time window for the timely therapy of severe trauma.
早期生活压力会在我们的基因上留下持久的记忆痕迹，并使我们终生面临抑郁的风险。早期生活压力会对小鼠的精氨酸加压素 (AVP) 基因进行表观遗传标记，从而支撑持续表达和增加下丘脑-垂体-肾上腺轴的活性，引发内分泌和行为改变，这些都是抑郁症的常见特征。这种表观遗传记忆通过表观遗传阅读器和写入器 MeCP2 的协调分为两个步骤进行。虽然 AVP 的早期去抑制是由神经元活动驱动的，该活动会导致 Ca2+/钙调蛋白激酶依赖性磷酸化和 MeCP2 的解离，但随后 AVP 增强子的低甲基化逐渐发展以维持去抑制。在恶性循环中，MeCP2 的占据与初始刺激脱钩，并导致早期生活经验在 DNA 甲基化水平上的硬编码。这些事件的顺序标志着从初步到持久、可能不可逆转的表观遗传记忆的转变，从而定义了对严重创伤进行及时治疗的关键时间窗口。
