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A measure of glucocorticoid load provided by DNA methylation of Fkbp5 in mice.

ABSTRACT: Given the contribution of cortisol dysregulation to neuropsychiatric and metabolic disorders, it is important to be able to accurately compute glucocorticoid burden, a measure of allostatic load. One major problem in calculating cortisol burden is that existing measures reflect cortisol exposure over a short duration and have not been proven to reliably quantify cortisol burden over weeks or months.We treated two cohorts of mice with corticosterone in the drinking water and determined the relationship between serial plasma corticosterone levels drawn over 4 weeks and the whole-blood DNA methylation (DNAm) changes in a specific glucocorticoid-sensitive gene, Fkbp5, determined at the end of the treatment period.We observed that the percent reduction in DNAm in the intron 1 region of Fkbp5 determined from a single blood draw strongly reflected average glucocorticoid burden generated weekly during the prior month of glucocorticoid exposure. There were also strong correlations in DNAm with glucocorticoid-induced end organ changes in spleen weight and visceral fat. We tested a subset of these animals for anxiety-like behavior in the elevated plus maze and found that DNAm in the blood also has predictive value in determining the behavioral consequences of glucocorticoid exposure.A whole-blood assessment of Fkbp5 gene methylation is a biomarker that integrates 4 weeks of glucocorticoid exposure and may be a useful measure in states of excess exposure. It will be important to determine if Fkbp5 DNAm changes can also be a biomarker of glucocorticoid burden during chronic social stress.

SUBMITTER: Lee RS

PROVIDER: S-EPMC3918452 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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A measure of glucocorticoid load provided by DNA methylation of Fkbp5 in mice.

Lee Richard S RS Tamashiro Kellie L K KL Yang Xiaoju X Purcell Ryan H RH Huo Yuqing Y Rongione Michael M Potash James B JB Wand Gary S GS

Psychopharmacology 20110421 1

<h4>Rationale</h4>Given the contribution of cortisol dysregulation to neuropsychiatric and metabolic disorders, it is important to be able to accurately compute glucocorticoid burden, a measure of allostatic load. One major problem in calculating cortisol burden is that existing measures reflect cortisol exposure over a short duration and have not been proven to reliably quantify cortisol burden over weeks or months.<h4>Method</h4>We treated two cohorts of mice with corticosterone in the drinkin ...[more]

PMID: 21509501

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Project description:Glucocorticoids may play a significant role in the etiology of neuropsychiatric illnesses. Abnormalities in plasma cortisol levels, glucocorticoid sensitivity, and HPA-axis function often accompany clinical symptoms of stress-related illnesses such as PTSD and depression. Of particular interest are genetic association studies that link single nucleotide polymorphisms of HPA-axis genes with illnesses only in the context of an early-life trauma exposure such as child abuse. These studies suggest that dysregulation of HPA-axis function can have lasting repercussions in shaping mood and anxiety, long after termination of the traumatic experience. As persistent glucocorticoid-induced loss of DNA methylation in FK506 binding protein 5 (Fkbp5) was previously observed in the hippocampus and blood and in the neuronal cell line HT-22, we asked whether these epigenetic alterations occur in non-neuronal, HPA-axis relevant cells. We used the pituitary adenoma cell line AtT-20 to demonstrate that the intronic enhancer region of Fkbp5 undergoes loss of DNA methylation in response to dexamethasone treatment in a dose-dependent manner. We also focused on the mouse hippocampal dentate gyrus to test whether these changes would be enriched in a region implicated in the HPA-axis stress response, neurogenesis, and synaptic plasticity. We observed an increase in enrichment of DNA methylation loss in the dentate gyrus, as compared to whole hippocampal tissues that were similarly treated with glucocorticoids. We then asked whether DNA methyltransferase 1 (Dnmt1), a methyltransferase enzyme involved in maintaining DNA methylation following cell division, is involved in the observed epigenetic alterations. We found a dose-dependent decrease of Dnmt1 expression in the AtT-20 cells following dexamethasone treatment, and a similar decrease in corticosterone-treated mouse hippocampus. Taken together, we provide evidence that these glucocorticoid-induced epigenetic alterations have a broader validity in non-neuronal cells and that they may involve the DNA methylation machinery.

Project description:The brain is a central hub for integration of internal and external conditions and, thus, a regulator of the stress response. Glucocorticoids are the essential communicators of this response. Aberrations in glucocorticoid signaling are a common symptom in patients with psychiatric disorders. The gene FKBP5 encodes a chaperone protein that functionally inhibits glucocorticoid signaling and, thus, contributes to the regulation of stress. In the context of childhood trauma, differential expression of FKBP5 has been found in psychiatric patients compared to controls. These variations in expression levels of FKBP5 were reported to be associated with differences in stress responsiveness in human carriers of the single nucleotide polymorphism (SNP) rs1360780. Understanding the mechanisms underlying FKBP5 polymorphism-associated glucocorticoid responsiveness in the CNS will lead to a better understanding of stress regulation or associated pathology. To study these mechanisms, two novel humanized mouse lines were generated. The lines carried either the risk (A/T) allele or the resilient (C/G) allele of rs1360780. Primary cells from CNS (astrocytes, microglia, and neurons) were analyzed for their basal expression levels of FKBP5 and their responsiveness to glucocorticoids. Differential expression of FKBP5 was found for these cell types and negatively correlated with the cellular glucocorticoid responsiveness. Astrocytes revealed the strongest transcriptional response, followed by microglia and neurons. Furthermore, the risk allele (A/T) was associated with greater induction of FKBP5 than the resilience allele. Novel FKBP5-humanized mice display differential glucocorticoid responsiveness due to a single intronic SNP. The vulnerability to stress signaling in the shape of glucocorticoids in the brain correlated with FKBP5 expression levels. The strong responsiveness of astrocytes to glucocorticoids implies astrocytes play a prominent role in the stress response, and in FKBP5-related differences in glucocorticoid signaling. The novel humanized mouse lines will allow for further study of the role that FKBP5 SNPs have in risk and resilience to stress pathology.

Project description:BACKGROUND:Disruption of the hypothalamic-pituitary-adrenal (HPA) axis, a neuroendocrine system associated with the stress response, has been hypothesized to contribute to obesity development. This may be mediated through epigenetic modulation of HPA axis-regulatory genes in response to metabolic stressors. The aim of this study was to investigate adipose tissue depot-specific DNA methylation differences in the glucocorticoid receptor (GR) and its co-chaperone, FK506-binding protein 51?kDa (FKBP5), both key modulators of the HPA axis. METHODS:Abdominal subcutaneous adipose tissue (ASAT) and gluteal subcutaneous adipose tissue (GSAT) biopsies were obtained from a sample of 27 obese and 27 normal weight urban-dwelling South African women. DNA methylation and gene expression were measured by pyrosequencing and quantitative real-time PCR, respectively. Spearman's correlation coefficients, orthogonal partial least-squares discriminant analysis and multivariable linear regression were performed to evaluate the associations between DNA methylation, messenger RNA (mRNA) expression and key indices of obesity and metabolic dysfunction. RESULTS:Two CpG dinucleotides within intron 7 of FKBP5 were hypermethylated in both ASAT and GSAT in obese compared to normal weight women, while no differences in GR methylation were observed. Higher percentage methylation of the two FKBP5 CpG sites correlated with adiposity (body mass index and waist circumference), insulin resistance (homeostasis model for insulin resistance, fasting insulin and plasma adipokines) and systemic inflammation (c-reactive protein) in both adipose depots. GR and FKBP5 mRNA levels were lower in GSAT, but not ASAT, of obese compared to normal weight women. Moreover, FKBP5 mRNA levels were inversely correlated with DNA methylation and positively associated with adiposity, metabolic and inflammatory parameters. CONCLUSIONS:These findings associate dysregulated FKBP5 methylation and mRNA expression with obesity and insulin resistance in South African women. Additional studies are required to assess the longitudinal association of FKBP5 with obesity and associated co-morbidities in large population-based samples.

Dataset Information

A measure of glucocorticoid load provided by DNA methylation of Fkbp5 in mice.

Publications

A measure of glucocorticoid load provided by DNA methylation of Fkbp5 in mice.

Similar Datasets

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