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Methylation at the CpG island shore region upregulates Nr3c1 promoter activity after early-life stress
Authors:Yvonne Bockmühl  Alexandre V Patchev  Arleta Madejska  Anke Hoffmann  Joao C Sousa  Nuno Sousa  Florian Holsboer  Osborne F X Almeida  Dietmar Spengler
Affiliation:1.Max Planck Institute of Psychiatry; Munich, Germany;2.Life and Health Sciences Research Institute (ICVS); School of Health Sciences; University of Minho; Braga, Portugal;3.ICVS/3B''s - PT Government Associate Laboratory; Braga/Guimarães, Portugal
Abstract:
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:CpG island shore   DNA methylation   early-life stress   glucocorticoid receptor   insulator   Yin Yang
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