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.
Keywords: Avp, arginine vasopressin; BPD, borderline personal disorder; CGI, CpG island; CUS, chronic unpredictable stress; ChIP, chromatin immunoprecipitation; CpG island shore; Crh, corticotropin releasing hormone; DNA methylation; Dusp1, dual specificity phosphatase 1; ELS, early-life stress; EMSA, electrophoretic mobility shift assay; Fkbp5, FK506 binding protein 51; GC, glucocorticoid; GR, glucocorticoid receptor; GRE, glucocorticoid response element; HPA, hypothalamic-pituitary-adrenal; MDD, major depressive disorder; PTSD, posttraumatic stress disorder; PVN, paraventricular nucleus; Pomc, pro-opiomelanocortin; Sgk1, serum glucocorticoid kinase 1; YY1, Yin Yang; Yin Yang; early-life stress; glucocorticoid receptor; insulator.