hide
Free keywords:
CpG island shore, DAN methylation, early life stress, glucocorticoid receptor, insulator, Yin Yang
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.
