The Janus face of DNA methylation in aging

Aging is arguably the most familiar yet least-well understood aspect of human biology. The role of epigenetics in aging and age-related diseases has gained interest given recent advances in the understanding of how epigenetic mechanisms mediate the interactions between the environment and the genetic blueprint. While current concepts generally view global deteriorations of epigenetic marks to insidiously impair cellular and molecular functions, an active role for epigenetic changes in aging has so far received little attention. In this regard, we have recently shown that early-life adversity induced specific changes in DNA methylation that were protected from an age-associated erasure and correlated with a phenotype well-known to increase the risk for age-related mental disorders. This finding strengthens the idea that DNA (de-)methylation is controlled by multiple mechanisms that might fulfill different, and partly contrasting, roles in the aging process

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

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.European Union Directorate General for Research & Innovation through the CRESCENDO Consortium (O.F.X.A. and D.S) and the NINA Initial Training Program (D.S. and O.F.X.A

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

<div><p>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 (<i>Nr3c1</i>) 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 <i>Nr3c1</i> 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 <i>Nr3c1</i> promoter, and assigns an insulating role to the CGI shore.</p></div