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Methylation at the CpG island shore region upregulates Nr3c1 promoter activity after early-life stress

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Bockmühl,  Yvonne
Max Planck Institute of Psychiatry, Max Planck Society;

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Patchev,  Alexandre V.
Max Planck Institute of Psychiatry, Max Planck Society;

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Madejska,  Arleta
Max Planck Institute of Psychiatry, Max Planck Society;

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Hoffmann,  Anke
Max Planck Institute of Psychiatry, Max Planck Society;

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Holsboer,  Florian
Max Planck Institute of Psychiatry, Max Planck Society;

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Almeida,  Osborne F. X.
Max Planck Institute of Psychiatry, Max Planck Society;

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Spengler,  Dietmar
Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Bockmühl, 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. doi:10.1080/15592294.2015.1017199.


Cite as: https://hdl.handle.net/11858/00-001M-0000-0028-E9A0-1
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.