Liu Patrick Z, Nusslock Robin
Department of Psychology, Northwestern University, Evanston, IL60208, USA.
Curr Genomics. 2018 Dec;19(8):653-664. doi: 10.2174/1389202919666171228164350.
Early life adversity is associated with both persistent disruptions in the hypothalamic-pituitary-adrenal (HPA) axis and psychiatric symptoms. Glucocorticoid receptors (GRs), which are encoded by the NR3C1 gene, bind to cortisol and other glucocorticoids to create a negative feedback loop within the HPA axis to regulate the body's neuroendocrine response to stress. Excess methylation of a promoter sequence within NR3C1 that attenuates GR expression, however, has been associated with both early life adversity and psychopathology. As critical regulators within the HPA axis, GRs and their epigenetic regulation may mediate the link between early life adversity and the onset of psychopathology. The present review discusses this work as one mechanism by which stress may get under the skin to disrupt HPA functioning at an epigenetic level and create long-lasting vulnerabilities in the stress regulatory system that subsequently predispose individuals to psychopathology. Spanning prenatal influences to critical periods of early life and adolescence, we detail the impact that early adversity has on GR expression, physiological responses to stress, and their implications for long-term stress management. We next propose a dual transmission hypothesis regarding both genomic and non-genomic mechanisms by which chronic and acute stress propagate through numerous generations. Lastly, we outline several directions for future research, including potential reversibility of methylation patterns and its functional implications, variation in behavior determined solely by NR3C1, and consensus on which specific promoter regions should be studied.
早年生活逆境与下丘脑-垂体-肾上腺（HPA）轴的持续紊乱及精神症状均有关联。由NR3C1基因编码的糖皮质激素受体（GRs）与皮质醇及其他糖皮质激素结合，在HPA轴内形成负反馈回路，以调节机体对应激的神经内分泌反应。然而，NR3C1基因内一个启动子序列的过度甲基化会减弱GR的表达，这与早年生活逆境和精神病理学均有关联。作为HPA轴内的关键调节因子，GRs及其表观遗传调控可能介导了早年生活逆境与精神病理学发病之间的联系。本综述将此项研究作为一种机制进行讨论，即应激可能通过表观遗传水平影响HPA功能，在应激调节系统中产生长期的易损性，进而使个体易患精神病理学疾病。从产前影响到早年生活及青春期的关键时期，我们详细阐述了早年逆境对GR表达、对应激的生理反应及其对长期应激管理的影响。接下来，我们提出了一个关于慢性和急性应激如何通过多代传播的基因组和非基因组机制的双重传递假说。最后，我们概述了未来研究的几个方向，包括甲基化模式的潜在可逆性及其功能意义、仅由NR3C1决定的行为差异，以及关于应研究哪些特定启动子区域的共识。
