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How Stress Gets Under the Skin: Early Life Adversity and Glucocorticoid Receptor Epigenetic Regulation
Current Genomics ( IF 2.6 ) Pub Date : 2018-10-19 , DOI: 10.2174/1389202919666171228164350
Patrick Z Liu 1 , Robin Nusslock 1
Affiliation  

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.

中文翻译:

压力如何深入皮肤:早年逆境和糖皮质激素受体表观遗传调控

早年的逆境与下丘脑-垂体-肾上腺(HPA)轴的持续破坏和精神症状有关。糖皮质激素受体 (GR) 由 NR3C1 基因编码,与皮质醇和其他糖皮质激素结合,在 HPA 轴内形成负反馈环,从而调节身体对压力的神经内分泌反应。然而,NR3C1 内启动子序列的过度甲基化会减弱 GR 的表达,这与早年的逆境和精神病理学有关。作为 HPA 轴内的关键调节因子,GR 及其表观遗传调节可能介导早期生活逆境与精神病理学发作之间的联系。本综述讨论了这项工作作为一种机制,通过这种机制,压力可能会深入皮肤,在表观遗传水平上扰乱 HPA 功能,并在压力调节系统中造成长期的脆弱性,从而使个体容易患上精神病理学。我们详细介绍了早期逆境对 GR 表达、对压力的生理反应及其对长期压力管理的影响,涵盖产前到生命早期和青春期关键时期的影响。接下来,我们提出了关于慢性和急性应激通过许多代传播的基因组和非基因组机制的双重传播假说。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含义、仅由 NR3C1 决定的行为变化,以及应研究哪些特定启动子区域的共识。
更新日期:2018-10-19
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