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TitleMethylation at the CpG island shore region upregulates Nr3c1 promoter activity after early-life stress
Author(s)Bockmühl, Yvonne
Patchev, Alexandre V.
Madejska, Arleta
Hoffmann, Anke
Sousa, João Carlos
Sousa, Nuno
Holsboer, Florian
Almeida, Osborne F. X.
Spengler, Dietmar
KeywordsCpG island shore
DNA methylation
Early-life stress
Glucocorticoid receptor
Yin Yang
Issue dateMar-2015
PublisherTaylor & Francis
CitationBockmühl, Y., Patchev, A. V., Madejska, A., Hoffmann, A., Sousa, J. C., Sousa, N., et. al.(2015). Methylation at the CpG island shore region upregulates Nr3c1 promoter activity after early-life stress. Epigenetics, 10(3), 247-257
Abstract(s)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.
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