Bockmühl Yvonne, Patchev Alexandre V, Madejska Arleta, Hoffmann Anke, Sousa Joao C, Sousa Nuno, Holsboer Florian, Almeida Osborne F X, Spengler Dietmar
a Max Planck Institute of Psychiatry ; Munich , Germany.
Epigenetics. 2015;10(3):247-57. doi: 10.1080/15592294.2015.1017199.
Early-life stress (ELS) induces long-lasting changes in gene expression conferring an increased risk for the development of stress-related mental disorders. Glucocorticoid receptors (GR) mediate the negative feedback actions of glucocorticoids (GC) in the paraventricular nucleus (PVN) of the hypothalamus and anterior pituitary and therefore play a key role in the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and the endocrine response to stress. We here show that ELS programs the expression of the GR gene (Nr3c1) by site-specific hypermethylation at the CpG island (CGI) shore in hypothalamic neurons that produce corticotropin-releasing hormone (Crh), thus preventing Crh upregulation under conditions of chronic stress. CpGs mapping to the Nr3c1 CGI shore region are dynamically regulated by ELS and underpin methylation-sensitive control of this region's insulation-like function via Ying Yang 1 (YY1) binding. Our results provide new insight into how a genomic element integrates experience-dependent epigenetic programming of the composite proximal Nr3c1 promoter, and assigns an insulating role to the CGI shore.
早年生活应激（ELS）会诱导基因表达发生持久变化，增加患应激相关精神障碍的风险。糖皮质激素受体（GR）介导糖皮质激素（GC）在下丘脑室旁核（PVN）和垂体前叶的负反馈作用，因此在调节下丘脑-垂体-肾上腺（HPA）轴以及对应激的内分泌反应中起关键作用。我们在此表明，ELS通过在产生促肾上腺皮质激素释放激素（Crh）的下丘脑神经元中，对CpG岛（CGI）边缘进行位点特异性高甲基化，来调控GR基因（Nr3c1）的表达，从而在慢性应激条件下阻止Crh上调。映射到Nr3c1 CGI边缘区域的CpG受ELS动态调控，并通过阴阳1（YY1）结合对该区域的绝缘样功能进行甲基化敏感控制。我们的研究结果为基因组元件如何整合复合近端Nr3c1启动子的经验依赖性表观遗传编程提供了新见解，并赋予了CGI边缘绝缘作用。
