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Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder.

ABSTRACT: Some individuals suffering from posttraumatic stress disorder (PTSD) exhibit lower basal salivary cortisol and higher glucocorticoid receptor (GR) sensitivity. Recent studies suggest that epigenetic mechanisms regulate the activity of cortisol and GR. As a means to combine and cross-validate those findings, we compared cortisol, GR expression and promoter methylation levels in peripheral T lymphocytes of healthy controls versus individuals endorsing a diagnosis of lifetime PTSD. Thirty subjects with lifetime (current or remitted) PTSD and 16 subjects never exposed to trauma were recruited. Salivary cortisol was collected at six time points over the course of a single weekday and analyzed utilizing a time-resolved fluorescence immunoassay. GR expression (GRtotal, 1B, 1C, 1F and 1H) was measured by quantitative RT-PCR. DNA methylation levels in human glucocorticoid receptor (hGR) 1B and 1C variant's promoter were quantified by epityper in T lymphocytes isolated by magnetic-assisted cell sorting. Individuals with lifetime PTSD have lower morning cortisol release, higher mRNA expression of hGRtotal, 1B, and 1C and lower overall methylation levels in hGR 1B and 1C promoters. Cortisol levels were inversely correlated with hGR 1B mRNA expression. Moreover, overall and CpG site-specific methylation levels were inversely correlated with hGRtotal and 1B mRNA expression. There was no difference between current and remitted PTSD across cortisol, GR expression mRNA and DNA methylation data. Traumatic events induce DNA methylation alterations in distinct promoters of hGR with transcriptional modifications that associate with hypoactive hypothalamus-pituitary-adrenal axis in individuals with PTSD. Our results also point toward an important role of hGR 1B variant in PTSD.

SUBMITTER: Labonte B

PROVIDER: S-EPMC3966043 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder.

Labonté B B Azoulay N N Yerko V V Turecki G G Brunet A A

Translational psychiatry 20140304

Some individuals suffering from posttraumatic stress disorder (PTSD) exhibit lower basal salivary cortisol and higher glucocorticoid receptor (GR) sensitivity. Recent studies suggest that epigenetic mechanisms regulate the activity of cortisol and GR. As a means to combine and cross-validate those findings, we compared cortisol, GR expression and promoter methylation levels in peripheral T lymphocytes of healthy controls versus individuals endorsing a diagnosis of lifetime PTSD. Thirty subjects ...[more]

PMID: 24594779

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Project description:Epigenetic marks, including DNA methylation, are modifiable molecular factors that may underlie mental disorders, especially responses to trauma, including the development of and resilience to posttraumatic stress disorder (PTSD). Previous work has identified differential DNA methylation at CpG dinucleotide sites genomewide between trauma exposed individuals with and without PTSD, suggesting a role for epigenetic potential-the capacity to epigenetically regulate behavior and physiology in response to lived experiences. The human species is characterized by an increased period of adaptive plasticity during brain development. The evolutionary history of epigenetic potential in relation to adaptive plasticity is currently unknown. Using phylogenetic methods and functional annotation analyses, we trace the evolution of over 7000 CpG dinucleotides, including 203 associated with PTSD, during the descent of humans in during mammalian evolution and characterize the biological significance of this evolution. We demonstrate that few (7%) PTSD-associated CpG sites are unique to humans, while the vast majority of sites have deep evolutionary origins: 73 and 93% were unambiguously present in the last common ancestor of humans/orangutans and humans/chimpanzees, respectively. Genes proximal to evolved PTSD-associated CpG sites revealed significant enrichment for immune function during recent human evolution and regulation of gene expression during more ancient periods of human evolution. Additionally, 765 putative transcription factor binding motifs (TFBMs) were identified that overlap with PTSD-associated CpG sites. Elucidation of the evolutionary history of PTSD-associated CpG sites may provide insights into the function and origin of epigenetic potential in trauma responses, generally, and PTSD, specifically. The human capacity to respond to trauma with stable physiologic and behavioral changes may be due to epigenetic potentials that are shared among many mammalian species.

Dataset Information

Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder.

Publications

Epigenetic modulation of glucocorticoid receptors in posttraumatic stress disorder.

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