Epigenetic regulation of the<i>glucocorticoid receptor</i>promoter 1<sub>7</sub>in adult rats

Witzmann, Simone R.; Turner, Jonathan D.; Mériaux, Sophie B.; Meijer, Onno C.; Muller, Claude P.

doi:10.4161/epi.22363

Cited by 80 publications

(73 citation statements)

References 48 publications

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“…No effects of acute stress were found on MR mRNA levels. DNA methylation analysis of this hippocampal subregion revealed a stress-induced increase in methylation in an area of the gene previously shown to be a target of stress-induced DNA methylation changes with long-term consequences for HPA axis and behavioural function [14,34,37]. This observation corresponds to the increased binding of the de novo methyltransferase DNMT3a with the stress-sensitive region GR area 2 in the Nr3c1 gene.…”

Section: Discussionmentioning

confidence: 86%

“…Similar phenomena have been observed in humans that experienced early-life abuse and neglect, and they are associated with mental health problems including suicide and depression later in life [20,21]. Additional studies have gone on to show rapid changes in methylation at specific CpG sites within this exon after acute stress in both the hippocampus and the paraventricular nucleus [14], as reviewed by Turecki and Meaney [22]. …”

Section: Introductionmentioning

confidence: 78%

“…Conflicting studies have shown GR mRNA levels to remain stable [10,11,12,13,14] or decrease [10,15,16] after a variety of stressors including forced swimming, restraint, Morris water maze exposure, and novelty stress. Thus far, stress-induced GR mRNA expression has generally been measured by either polymerase chain reaction (PCR) analysis of whole hippocampi [10,13] or via in situ hybridisation [11,12,14,15]. The former method neglects differences in the subregional distribution of GRs, and the latter is semi-quantitative and therefore may not be sensitive enough to detect moderate stress-related changes in GR expression.…”

Section: Introductionmentioning

confidence: 99%

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Rapid Down-Regulation of Glucocorticoid Receptor Gene Expression in the Dentate Gyrus after Acute Stress in vivo: Role of DNA Methylation and MicroRNA Activity

et al. 2016

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Background: Although glucocorticoid receptors (GRs) in the hippocampus play a vital role in the regulation of physiological and behavioural responses to stress, the regulation of receptor expression remains unclear. This work investigates the molecular mechanisms underpinning stress-induced changes in hippocampal GR mRNA levels in vivo. Methods: Male Wistar rats were killed either under baseline conditions or after forced swim stress (FSS; 15 min in 25°C water). Rat hippocampi were micro-dissected (for mRNA, microRNA, and DNA methylation analysis) or frozen whole (for chromatin immunoprecipitation). In an additional experiment, rats were pre-treated with RU486 (a GR antagonist) or vehicle. Results: FSS evoked a dentate gyrus-specific reduction in GR mRNA levels. This was related to an increased DNMT3a protein association with a discreet region of the Nr3c1 (GR gene) promoter, shown here to undergo increased DNA methylation after FSS. FSS also caused a time-dependent increase in the expression of miR-124a, a microRNA known to reduce GR mRNA expression, which was inversely correlated with a reduction in GR mRNA levels 30 min after FSS. FSS did not affect GR binding to a putative negative glucocorticoid response element within the Nr3c1 gene. Conclusions: Acute stress results in decreased GR mRNA expression specifically in the dentate gyrus. Our results indicate that a complex interplay of multiple molecular mechanisms - including increased DNA methylation of discrete CpG residues within the Nr3c1 gene, most likely facilitated by DNMT3a, and increased expression of miR-124a - could be responsible for these changes.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

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Rapid Down-Regulation of Glucocorticoid Receptor Gene Expression in the Dentate Gyrus after Acute Stress in vivo: Role of DNA Methylation and MicroRNA Activity

et al. 2016

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“…Age dependence of stress vulnerability is illustrated by more recent studies on the well-established example of changed GR promoter methylation in response to maternal care or early life stress. These suggest that a shift in the timing of the stressor to adulthood does not lead to the same effects on the rodent I 7 GR promoter, or the human analog GR 1F promoter, methylation (Alt et al, 2010;Witzmann et al, 2012).…”

Section: Signaling Through Small Non-coding Rnas In Response To Stressmentioning

confidence: 86%

Epigenetics of Stress-Related Psychiatric Disorders and Gene × Environment Interactions

Klengel

Binder

2015

Neuron

283

184

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A deeper understanding of the pathomechanisms leading to stress-related psychiatric disorders is important for the development of more efficient preventive and therapeutic strategies. Epidemiological studies indicate a combined contribution of genetic and environmental factors in the risk for disease. The environment, particularly early life severe stress or trauma, can lead to lifelong molecular changes in the form of epigenetic modifications that can set the organism off on trajectories to health or disease. Epigenetic modifications are capable of shaping and storing the molecular response of a cell to its environment as a function of genetic predisposition. This provides a potential mechanism for gene-environment interactions. Here, we review epigenetic mechanisms associated with the response to stress and trauma exposure and the development of stress-related psychiatric disorders. We also look at how they may contribute to our understanding of the combined effects of genetic and environmental factors in shaping disease risk.

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“…For example, chronic stress alters the level of circulating glucocorticoids and DNA methylation at CpG islands on the glucocorticoid receptor (NR3C1) gene promoter in specific regions of the brain, resulting in altered NR3C1 expression and function in the HPA axis. 13, 14 Little is presently known about the role of epigenetic mechanisms in modulating peripheral sensory nerve function. A subset of patients with irritable bowel syndrome (IBS) demonstrate altered expression of specific noncoding microRNAs in intestinal mucosa that inhibit glutamine synthetase, supporting a potential role for epigenetic pathways in this disorder.…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Regulation of Genes That Modulate Chronic Stress-Induced Visceral Pain in the Peripheral Nervous System

Hong¹,

Zheng²,

2015

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BACKGROUNDS & AIMS Chronic stress alters the hypothalamic–pituitary–adrenal axis, increases gut motility, and increases perception of visceral pain. We investigated whether epigenetic mechanisms regulate chronic stress-induced visceral pain in the peripheral nervous systems of rats. METHODS Male rats were subjected to 1 hr water-avoidance stress each day, or given daily subcutaneous injections of corticosterone, for 10 consecutive days. L4–L5 and L6–S2 dorsal root ganglia (DRG) were collected and compared between stressed and control rats (placed for 1 hour each day in a tank without water). Levels of cannabinoid receptor 1 (CNR1), DNA (cytosine-5-)-methyltransferase 1 (DNMT1), transient receptor potential vanilloid type 1 (TRPV1), and EP300 were knocked down in DRG neurons in situ with small interfering RNAs. We measured DNA methylation and histone acetylation at genes encoding the glucocorticoid receptor (NR3C1), CNR1, and TRPV1. Visceral pain was measured in response to colorectal distention. RESULTS Chronic stress was associated with increased methylation of the Nr3c1 promoter and reduced expression of this gene in L6–S2, but not L4–L5, DRGs. Stress was also associated with upregulation in DNMT1-associated methylation of the Cnr1 promoter and downregulation of glucocorticoid receptor-mediated expression of CNR1 in L6–S2, but not L4–L5, DRGs. Concurrently, chronic stress increased expression of the histone acetyltransferase EP300 and increased histone acetylation at the Trpv1 promoter and expression of the TRPV1 receptor in L6–S2 DRG neurons. Knockdown of DNMT1 and EP300 in L6–S2 DRG neurons of rats reduced DNA methylation and histone acetylation, respectively, and prevented chronic stress-induced increases in visceral pain. CONCLUSIONS Chronic stress increases DNA methylation and histone acetylation of genes that regulate visceral pain sensation in the peripheral nervous system of rats. Blocking epigenetic regulatory pathways in specific regions of the spinal cord might be developed to treat patients with chronic abdominal pain.

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Epigenetic regulation of theglucocorticoid receptorpromoter 1₇in adult rats

Cited by 80 publications

References 48 publications

Rapid Down-Regulation of Glucocorticoid Receptor Gene Expression in the Dentate Gyrus after Acute Stress in vivo: Role of DNA Methylation and MicroRNA Activity

Rapid Down-Regulation of Glucocorticoid Receptor Gene Expression in the Dentate Gyrus after Acute Stress in vivo: Role of DNA Methylation and MicroRNA Activity

Epigenetics of Stress-Related Psychiatric Disorders and Gene × Environment Interactions

Epigenetic Regulation of Genes That Modulate Chronic Stress-Induced Visceral Pain in the Peripheral Nervous System

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Epigenetic regulation of theglucocorticoid receptorpromoter 17in adult rats

Cited by 80 publications

References 48 publications

Rapid Down-Regulation of Glucocorticoid Receptor Gene Expression in the Dentate Gyrus after Acute Stress in vivo: Role of DNA Methylation and MicroRNA Activity

Rapid Down-Regulation of Glucocorticoid Receptor Gene Expression in the Dentate Gyrus after Acute Stress in vivo: Role of DNA Methylation and MicroRNA Activity

Epigenetics of Stress-Related Psychiatric Disorders and Gene × Environment Interactions

Epigenetic Regulation of Genes That Modulate Chronic Stress-Induced Visceral Pain in the Peripheral Nervous System

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Epigenetic regulation of theglucocorticoid receptorpromoter 1₇in adult rats