Mice with an Increased Glucocorticoid Receptor Gene Dosage Show Enhanced Resistance to Stress and Endotoxic Shock

ABSTRACT Targeted mutagenesis of the glucocorticoid receptor has revealed an essential function for survival and the regulation of multiple physiological processes. To investigate the effects of an increased gene dosage of the receptor, we have generated transgenic mice carrying two additional copies of the glucocorticoid receptor gene by using a yeast artificial chromosome. Interestingly, overexpression of the glucocorticoid receptor alters the basal regulation of the hypothalamo-pituitary-adrenal axis, resulting in reduced expression of corticotropin-releasing hormone and adrenocorticotrope hormone and a fourfold reduction in the level of circulating glucocorticoids. In addition, primary thymocytes obtained from transgenic mice show an enhanced sensitivity to glucocorticoid-induced apoptosis. Finally, analysis of these mice under challenge conditions revealed that expression of the glucocorticoid receptor above wild-type levels leads to a weaker response to restraint stress and a strongly increased resistance to lipopolysaccharide-induced endotoxic shock. These results underscore the importance of tight regulation of glucocorticoid receptor expression for the control of physiological and pathological processes. Furthermore, they may explain differences in the susceptibility of humans to inflammatory diseases and stress, depending on individual prenatal and postnatal experiences known to influence the expression of the glucocorticoid receptor.

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Tissue-, sex-, and age-specific DNA methylation of rat glucocorticoid receptor gene promoter and insulin-like growth factor 2 imprinting control region

Physiological Genomics ◽

10.1152/physiolgenomics.00009.2017 ◽

2017 ◽

Vol 49 (11) ◽

pp. 690-702 ◽

Cited By ~ 7

Author(s):

Ogechukwu Brenda Agba ◽

Ludwig Lausser ◽

Klaus Huse ◽

Christoph Bergmeier ◽

Niels Jahn ◽

...

Keyword(s):

Dna Methylation ◽

Glucocorticoid Receptor ◽

Control Region ◽

Cpg Island ◽

Receptor Gene ◽

Epigenetic Modifications ◽

Receptor Expression ◽

Glucocorticoid Receptor Gene ◽

Imprinting Control Region ◽

Methylation Patterns

Tissue-, sex-, and age-specific epigenetic modifications such as DNA methylation are largely unknown. Changes in DNA methylation of the glucocorticoid receptor gene ( NR3C1) and imprinting control region (ICR) of IGF2 and H19 genes during the lifespan are particularly interesting since these genes are susceptible to epigenetic modifications by prenatal stress or malnutrition. They are important regulators of development and aging. Methylation changes of NR3C1 affect glucocorticoid receptor expression, which is associated with stress sensitivity and stress-related diseases predominantly occurring during aging. Methylation changes of IGF2/H19 affect growth trajectory and nutrient use with risk of metabolic syndrome. Using a locus-specific approach, we characterized DNA methylation patterns of different Nr3c1 promoters and Igf2/H19 ICR in seven tissues of rats at 3, 9, and 24 mo of age. We found a complex pattern of locus-, tissue-, sex-, and age-specific DNA methylation. Tissue-specific methylation was most prominent at the shores of the Nr3c1 CpG island (CGI). Sex-specific differences in methylation peaked at 9 mo. During aging, Nr3c1 predominantly displayed hypomethylation mainly in females and at shores, whereas hypermethylation occurred within the CGI. Igf2/H19 ICR exhibited age-related hypomethylation occurring mainly in males. Methylation patterns of Nr3c1 in the skin correlated with those in the cortex, hippocampus, and hypothalamus. Skin may serve as proxy for methylation changes in central parts of the hypothalamic-pituitary-adrenal axis and hence for vulnerability to stress- and age-associated diseases. Thus, we provide in-depth insight into the complex DNA methylation changes of rat Nr3c1 and Igf2/H19 during aging that are tissue and sex specific.

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Environmental programming of stress responses through DNA methylation: life at the interface between a dynamic environment and a fixed genome

Dialogues in Clinical Neuroscience ◽

10.31887/dcns.2005.7.2/mmeaney ◽

2005 ◽

Vol 7 (2) ◽

pp. 103-123 ◽

Cited By ~ 59

Keyword(s):

Dna Methylation ◽

Glucocorticoid Receptor ◽

Stress Responses ◽

Chromatin Structure ◽

Causal Relation ◽

Epigenetic Modification ◽

Receptor Gene ◽

Receptor Expression ◽

Critical Question ◽

Glucocorticoid Receptor Gene

Early experience permanently alters behavior and physiology. These effects are, in part, mediated by sustained alterations in gene expression in selected brain regions. The critical question concerns the mechanism of these environmental "programming" effects. We examine this issue with an animal model that studies the consequences of variations in mother-infant interactions on the development of individual differences in behavioral and endocrine responses to stress in adulthood. Increased levels of pup licking/grooming by rat mothers in the first week of life alter DNA structure at a glucocorticoid receptor gene promoter in the hippocampus of the offspring. Differences in the DNA methylation pattern between the offspring of high- and low-licking/grooming mothers emerge over the first week of life; they are reversed with cross-fostering; they persist into adulthood; and they are associated with altered histone acetylation and transcription factor (nerve growth factor-induced clone A [NGFIA]) binding to the glucocorticoid receptor promoter. DNA methylation alters glucocorticoid receptor expression through modifications of chromatin structure. Pharmacological reversal of the effects on chromatin structure completely eliminates the effects of maternal care on glucocorticoid receptor expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, thus suggesting a causal relation between the maternally induced, epigenetic modification of the glucocorticoid receptor gene and the effects on stress responses in the offspring. These findings demonstrate that the structural modifications of the DNA can be established through environmental programming and that, in spite of the inherent stability of this epigenomic marker, it is dynamic and potentially reversible.

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