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

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.

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

Physiological Genomics ◽

10.1152/physiolgenomics.00201.2009 ◽

2010 ◽

Vol 42 (2) ◽

pp. 177-189 ◽

Cited By ~ 34

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.

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Effects of the Social Environment and Stress on Glucocorticoid Receptor Gene Methylation: A Systematic Review

Biological Psychiatry ◽

10.1016/j.biopsych.2014.11.022 ◽

2016 ◽

Vol 79 (2) ◽

pp. 87-96 ◽

Cited By ~ 296

Author(s):

Gustavo Turecki ◽

Michael J. Meaney

Keyword(s):

Systematic Review ◽

Glucocorticoid Receptor ◽

Social Environment ◽

Receptor Gene ◽

Gene Methylation ◽

The Social ◽

Glucocorticoid Receptor Gene

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998 Glucocorticoid Receptor Gene Methylation is a Potential Biomarker of Irritable Bowel Syndrome

Gastroenterology ◽

10.1016/s0016-5085(12)60663-5 ◽

2012 ◽

Vol 142 (5) ◽

pp. S-176-S-177 ◽

Cited By ~ 2

Author(s):

Lin Chang ◽

Dimitrios Iliopoulos ◽

Christos Polytarchou ◽

Melissa Alberto ◽

Wendy Shih ◽

...

Keyword(s):

Irritable Bowel Syndrome ◽

Glucocorticoid Receptor ◽

Receptor Gene ◽

Gene Methylation ◽

Potential Biomarker ◽

Glucocorticoid Receptor Gene ◽

Irritable Bowel

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Glucocorticoid receptor gene methylation moderates the association of childhood trauma and cortisol stress reactivity

Psychoneuroendocrinology ◽

10.1016/j.psyneuen.2018.01.020 ◽

2018 ◽

Vol 90 ◽

pp. 68-75 ◽

Cited By ~ 19

Author(s):

Nina Alexander ◽

Clemens Kirschbaum ◽

Matthis Wankerl ◽

Benjamin J. Stauch ◽

Tobias Stalder ◽

...

Keyword(s):

Glucocorticoid Receptor ◽

Childhood Trauma ◽

Stress Reactivity ◽

Receptor Gene ◽

Gene Methylation ◽

Glucocorticoid Receptor Gene

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Methylation of exons 1D, 1F, and 1H of the glucocorticoid receptor gene promoter and exposure to adversity in preschool-aged children

Development and Psychopathology ◽

10.1017/s0954579415000176 ◽

2015 ◽

Vol 27 (2) ◽

pp. 577-585 ◽

Cited By ~ 33

Author(s):

Audrey R. Tyrka ◽

Stephanie H. Parade ◽

Nicole M. Eslinger ◽

Carmen J. Marsit ◽

Corina Lesseur ◽

...

Keyword(s):

Glucocorticoid Receptor ◽

Animal Studies ◽

Receptor Gene ◽

Gene Promoter ◽

Ethnically Diverse ◽

Gene Methylation ◽

Bisulfite Pyrosequencing ◽

Glucocorticoid Receptor Gene ◽

History Of ◽

Record Review

AbstractEpigenetic modifications to the genome are a key mechanism involved in the biological encoding of experience. Animal studies and a growing body of literature in humans have shown that early adversity is linked to methylation of the gene for the glucocorticoid receptor (GR), which is a key regulator of the hypothalamic–pituitary–adrenal axis as well as a broad range of physiological systems including metabolic and immune function. One hundred eighty-four families participated, including n = 74 with child welfare documentation of moderate-severe maltreatment in the past 6 months. Children ranged in age from 3 to 5 years, and were racially and ethnically diverse. Structured record review and interviews in the home were used to assess a history of maltreatment, other traumas, and contextual life stressors, and a composite variable assessed the number exposures to these adversities. Methylation of regions 1D, 1F, and 1H of the GR gene was measured via sodium bisulfite pyrosequencing. The composite measure of adversity was positively correlated with methylation at exons 1D and 1F in the promoter of the GR gene. Individual stress measures were significantly associated with a several CpG sites in these regions. GR gene methylation may be a mechanism of the biobehavioral effects of adverse exposures in young children.

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