scholarly journals Early life trauma, depression and the glucocorticoid receptor gene – an epigenetic perspective

2015 ◽  
Vol 45 (16) ◽  
pp. 3393-3410 ◽  
Author(s):  
C. Smart ◽  
G. Strathdee ◽  
S. Watson ◽  
C. Murgatroyd ◽  
R. H. McAllister-Williams
Keyword(s):  
Dna Methylation ◽  
Glucocorticoid Receptor ◽  
Hpa Axis ◽  
Early Life ◽  
Epigenetic Modification ◽  
Receptor Gene ◽  
Unipolar Depression ◽  
Tissue Cell ◽  
Glucocorticoid Receptor Gene ◽  
Early Life Trauma

Background.Hopes to identify genetic susceptibility loci accounting for the heritability seen in unipolar depression have not been fully realized. Family history remains the ‘gold standard’ for both risk stratification and prognosis in complex phenotypes such as depression. Meanwhile, the physiological mechanisms underlying life-event triggers for depression remain opaque. Epigenetics, comprising heritable changes in gene expression other than alterations of the nucleotide sequence, may offer a way to deepen our understanding of the aetiology and pathophysiology of unipolar depression and optimize treatments. A heuristic target for exploring the relevance of epigenetic changes in unipolar depression is the hypothalamic–pituitary–adrenal (HPA) axis. The glucocorticoid receptor (GR) gene (NR3C1) has been found to be susceptible to epigenetic modification, specifically DNA methylation, in the context of environmental stress such as early life trauma, which is an established risk for depression later in life.Method.In this paper we discuss the progress that has been made by studies that have investigated the relationship between depression, early trauma, the HPA axis and the NR3C1 gene. Difficulties with the design of these studies are also explored.Results.Future efforts will need to comprehensively address epigenetic natural histories at the population, tissue, cell and gene levels. The complex interactions between the epigenome, genome and environment, as well as ongoing nosological difficulties, also pose significant challenges.Conclusions.The work that has been done so far is nevertheless encouraging and suggests potential mechanistic and biomarker roles for differential DNA methylation patterns in NR3C1 as well as novel therapeutic targets.

scholarly journals Developmental conditions modulate DNA methylation at the glucocorticoid receptor gene with cascading effects on expression and corticosterone levels in zebra finches

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Blanca Jimeno ◽  
Michaela Hau ◽  
Elena Gómez-Díaz ◽  
Simon Verhulst
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Glucocorticoid Receptor ◽  
Early Life ◽  
Receptor Gene ◽  
Regulatory Region ◽  
Long Term Effects ◽  
Glucocorticoid Receptor Gene ◽  
Developmental Conditions

Abstract Developmental conditions can impact the adult phenotype via epigenetic changes that modulate gene expression. In mammals, methylation of the glucocorticoid receptor gene Nr3c1 has been implicated as mediator of long-term effects of developmental conditions, but this evidence is limited to humans and rodents, and few studies have simultaneously tested for associations between DNA methylation, gene expression and phenotype. Adverse environmental conditions during early life (large natal brood size) or adulthood (high foraging costs) exert multiple long-term phenotypic effects in zebra finches, and we here test for effects of these manipulations on DNA methylation and expression of the Nr3c1 gene in blood. Having been reared in a large brood induced higher DNA methylation of the Nr3c1 regulatory region in adulthood, and this effect persisted over years. Nr3c1 expression was negatively correlated with methylation at 2 out of 8 CpG sites, and was lower in hard foraging conditions, despite foraging conditions having no effect on Nr3c1 methylation at our target region. Nr3c1 expression also correlated with glucocorticoid traits: higher expression level was associated with lower plasma baseline corticosterone concentrations and enhanced corticosterone reactivity. Our results suggest that methylation of the Nr3c1 regulatory region can contribute to the mechanisms underlying the emergence of long-term effects of developmental conditions in birds, but in our system current adversity dominated over early life experiences with respect to receptor expression.

A Tissue Comparison of DNA Methylation of the Glucocorticoid Receptor Gene (Nr3c1) in European Starlings

2019 ◽  
Vol 59 (2) ◽  
pp. 264-272 ◽  
Author(s):  
Stefanie J Siller ◽  
Dustin R Rubenstein
Keyword(s):  
Dna Methylation ◽  
Glucocorticoid Receptor ◽  
Glucocorticoid Receptors ◽  
Epigenetic Modification ◽  
Receptor Gene ◽  
Putative Promoter ◽  
European Starlings ◽  
Cpg Sites ◽  
Glucocorticoid Receptor Gene ◽  
The Brain

Abstract Negative feedback of the vertebrate stress response via the hypothalamic–pituitary–adrenal (HPA) axis is regulated by glucocorticoid receptors in the brain. Epigenetic modification of the glucocorticoid receptor gene (Nr3c1), including DNA methylation of the promoter region, can influence expression of these receptors, impacting behavior, physiology, and fitness. However, we still know little about the long-term effects of these modifications on fitness. To better understand these fitness effects, we must first develop a non-lethal method to assess DNA methylation in the brain that allows for multiple measurements throughout an organism’s lifetime. In this study, we aimed to determine if blood is a viable biomarker for Nr3c1 DNA methylation in two brain regions (hippocampus and hypothalamus) in adult European starlings (Sturnus vulgaris). We found that DNA methylation of CpG sites in the complete Nr3c1 putative promoter varied among tissue types and was lowest in blood. Although we identified a similar cluster of correlated Nr3c1 putative promoter CpG sites within each tissue, this cluster did not show any correlation in DNA methylation among tissues. Additional studies should consider the role of the developmental environment in producing epigenetic modifications in different tissues.

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

2005 ◽  
Vol 7 (2) ◽  
pp. 103-123 ◽  
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.

Intrauterine growth retardation affects expression and epigenetic characteristics of the rat hippocampal glucocorticoid receptor gene

2010 ◽  
Vol 42 (2) ◽  
pp. 177-189 ◽  
Author(s):  
Xingrao Ke ◽  
Michelle E. Schober ◽  
Robert A. McKnight ◽  
Shannon O'Grady ◽  
Diana Caprau ◽  
...  
Keyword(s):  
Glucocorticoid Receptor ◽  
Hpa Axis ◽  
Growth Retardation ◽  
Intrauterine Growth Retardation ◽  
Receptor Gene ◽  
Altered Expression ◽  
Time Points ◽  
Intrauterine Growth ◽  
Mrna Variant ◽  
Glucocorticoid Receptor Gene

Studies in humans and rats suggest that intrauterine growth retardation (IUGR) permanently resets the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis reprogramming may involve persistently altered expression of the hippocampal glucocorticoid receptor (hpGR), an important regulator of HPA axis reactivity. Persistent alteration of gene expression, long after the inciting event, is thought to be mediated by epigenetic mechanisms that affect mRNA and mRNA variant expression. GR mRNA variants in both humans and rats include eleven 5′-end variants and GRα, the predominant 3′-end variant. The 3′-end variants associated with glucocorticoid resistance in humans (GRβ, GRγ, GRA, and GRP) have not been reported in rats. We hypothesized that in the rat hippocampus IUGR would decrease total GR mRNA, increase GRβ, GRγ, GRA, and GRP, and affect epigenetics of the GR gene at birth (D0) and at 21 days of life (D21). IUGR increased hpGR and exon 1.7 hpGR mRNA in males at D0 and D21, associated with increased trimethyl H3/K4 at exon 1.7 at both time points. IUGR also increased hpGRγ in males at D0 and D21, associated with increased acetyl H3/K9 at exon 3 at both time points. hpGRA increased in female IUGR rats at D0 and D21. In addition, our data support the existence of hpGRβ and hpGRP in the rat. IUGR has sex-specific, persistent effects on GR expression and its histone code. We speculate that postnatal changes in hippocampal GR variant and total mRNA expression may underlie IUGR-associated HPA axis reprogramming.

Glucocorticoid receptor gene methylation and HPA-axis regulation in adolescents. The TRAILS study

2015 ◽  
Vol 58 ◽  
pp. 46-50 ◽  
Author(s):  
Lisette J. van der Knaap ◽  
Albertine J. Oldehinkel ◽  
Frank C. Verhulst ◽  
Floor V.A. van Oort ◽  
Harriëtte Riese
Keyword(s):  
Glucocorticoid Receptor ◽  
Hpa Axis ◽  
Receptor Gene ◽  
Gene Methylation ◽  
Glucocorticoid Receptor Gene

scholarly journals DNA methylation of the glucocorticoid receptor gene predicts substance use in adolescence: longitudinal data from over 1000 young individuals

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Elena Raffetti ◽  
Philippe Anastasios Melas ◽  
Anton Jonatan Landgren ◽  
Filip Andersson ◽  
Yvonne Forsell ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Substance Use ◽  
Glucocorticoid Receptor ◽  
Life Stress ◽  
Early Life ◽  
Predictor Variable ◽  
Early Life Stress ◽  
Glucocorticoid Receptor Gene ◽  
Self Reports ◽  
Middle Adolescence

AbstractEarly life stress has been linked to increased methylation of the Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1) gene, which codes for the glucocorticoid receptor. Moreover, early life stress has been associated with substance use initiation at a younger age, a risk factor for developing substance use disorders. However, no studies to date have investigated whether NR3C1 methylation can predict substance use in young individuals. This study included adolescents 13–14 years of age that reported no history of substance use at baseline, (N = 1041; males = 46%). Participants contributed saliva DNA samples and were followed in middle adolescence as part of KUPOL, a prospective cohort study of 7th-grade students in Sweden. Outcome variables were self-reports of (i) recent use, (ii) lifetime use, and (iii) use duration of (a) alcohol, (b) tobacco products, (c) cannabis, or (d) any substance. Outcomes were measured annually for three consecutive years. The predictor variable was DNA methylation at the exon 1 F locus of NR3C1. Risk and rate ratios were calculated as measures of association, with or without adjustment for internalizing symptoms and parental psychiatric disorders. For a subset of individuals (N = 320), there were also morning and afternoon salivary cortisol measurements available that were analyzed in relation to NR3C1 methylation levels. Baseline NR3C1 hypermethylation associated with future self-reports of recent use and use duration of any substance, before and after adjustment for potential confounders. The overall estimates were attenuated when considering lifetime use. Sex-stratified analyses revealed the strongest association for cigarette use in males. Cortisol analyses revealed associations between NR3C1 methylation and morning cortisol levels. Findings from this study suggest that saliva NR3C1 hypermethylation can predict substance use in middle adolescence. Additional longitudinal studies are warranted to confirm these findings.

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

2017 ◽  
Vol 49 (11) ◽  
pp. 690-702 ◽  
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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