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      Epigenetic Biomarkers as Predictors and Correlates of Symptom Improvement Following Psychotherapy in Combat Veterans with PTSD

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          Abstract

          Epigenetic alterations offer promise as diagnostic or prognostic markers, but it is not known whether these measures associate with, or predict, clinical state. These questions were addressed in a pilot study with combat veterans with PTSD to determine whether cytosine methylation in promoter regions of the glucocorticoid related NR3C1 and FKBP51 genes would predict or associate with treatment outcome. Veterans with PTSD received prolonged exposure (PE) psychotherapy, yielding responders ( n = 8), defined by no longer meeting diagnostic criteria for PTSD, and non-responders ( n = 8). Blood samples were obtained at pre-treatment, after 12 weeks of psychotherapy (post-treatment), and after a 3-month follow-up. Methylation was examined in DNA extracted from lymphocytes. Measures reflecting glucocorticoid receptor (GR) activity were also obtained (i.e., plasma and 24 h-urinary cortisol, plasma ACTH, lymphocyte lysozyme IC 50-DEX, and plasma neuropeptide-Y). Methylation of the GR gene ( NR3C1) exon 1F promoter assessed at pre-treatment predicted treatment outcome, but was not significantly altered in responders or non-responders at post-treatment or follow-up. In contrast, methylation of the FKBP5 gene ( FKBP51) exon 1 promoter region did not predict treatment response, but decreased in association with recovery. In a subset, a corresponding group difference in FKBP5 gene expression was observed, with responders showing higher gene expression at post-treatment than non-responders. Endocrine markers were also associated with the epigenetic markers. These preliminary observations require replication and validation. However, the results support research indicating that some glucocorticoid related genes are subject to environmental regulation throughout life. Moreover, psychotherapy constitutes a form of “environmental regulation” that may alter epigenetic state. Finally, the results further suggest that different genes may be associated with prognosis and symptom state, respectively.

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          Most cited references52

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          Epigenetic programming by maternal behavior.

          Here we report that increased pup licking and grooming (LG) and arched-back nursing (ABN) by rat mothers altered the offspring epigenome at a glucocorticoid receptor (GR) gene promoter in the hippocampus. Offspring of mothers that showed high levels of LG and ABN were found to have differences in DNA methylation, as compared to offspring of 'low-LG-ABN' mothers. These differences emerged over the first week of life, were reversed with cross-fostering, persisted into adulthood and were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter. Central infusion of a histone deacetylase inhibitor removed the group differences in histone acetylation, DNA methylation, NGFI-A binding, GR expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, suggesting a causal relation among epigenomic state, GR expression and the maternal effect on stress responses in the offspring. Thus we show that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible.
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            Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions.

            Although the fact that genetic predisposition and environmental exposures interact to shape development and function of the human brain and, ultimately, the risk of psychiatric disorders has drawn wide interest, the corresponding molecular mechanisms have not yet been elucidated. We found that a functional polymorphism altering chromatin interaction between the transcription start site and long-range enhancers in the FK506 binding protein 5 (FKBP5) gene, an important regulator of the stress hormone system, increased the risk of developing stress-related psychiatric disorders in adulthood by allele-specific, childhood trauma-dependent DNA demethylation in functional glucocorticoid response elements of FKBP5. This demethylation was linked to increased stress-dependent gene transcription followed by a long-term dysregulation of the stress hormone system and a global effect on the function of immune cells and brain areas associated with stress regulation. This identification of molecular mechanisms of genotype-directed long-term environmental reactivity will be useful for designing more effective treatment strategies for stress-related disorders.
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              The link between childhood trauma and depression: insights from HPA axis studies in humans.

              Childhood trauma is a potent risk factor for developing depression in adulthood, particularly in response to additional stress. We here summarize results from a series of clinical studies suggesting that childhood trauma in humans is associated with sensitization of the neuroendocrine stress response, glucocorticoid resistance, increased central corticotropin-releasing factor (CRF) activity, immune activation, and reduced hippocampal volume, closely paralleling several of the neuroendocrine features of depression. Neuroendocrine changes secondary to early-life stress likely reflect risk to develop depression in response to stress, potentially due to failure of a connected neural circuitry implicated in emotional, neuroendocrine and autonomic control to compensate in response to challenge. However, not all of depression is related to childhood trauma and our results suggest the existence of biologically distinguishable subtypes of depression as a function of childhood trauma that are also responsive to differential treatment. Other risk factors, such as female gender and genetic dispositions, interfere with components of the stress response and further increase vulnerability for depression. Similar associations apply to a spectrum of other psychiatric and medical disorders that frequently coincide with depression and are aggravated by stress. Taken together, this line of evidence demonstrates that psychoneuroendocrine research may ultimately promote optimized clinical care and help prevent the adverse outcomes of childhood trauma.
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                Author and article information

                Journal
                Front Psychiatry
                Front Psychiatry
                Front. Psychiatry
                Frontiers in Psychiatry
                Frontiers Media S.A.
                1664-0640
                19 July 2013
                27 September 2013
                2013
                : 4
                : 118
                Affiliations
                [1] 1Traumatic Stress Studies Division, Department of Psychiatry, Icahn School of Medicine at Mount Sinai , New York, NY, USA
                [2] 2Mental Health Care Center, PTSD Clinical Research Program and Laboratory of Clinical Neuroendocrinology and Neurochemistry, James J. Peters Veterans Affairs Medical Center , Bronx, NY, USA
                [3] 3Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai , New York, NY, USA
                [4] 4Laboratory of Molecular Neuropsychiatry, Department of Psychiatry, Icahn School of Medicine at Mount Sinai , New York, NY, USA
                [5] 5Department of Genetics and Genomics Sciences, Icahn School of Medicine at Mount Sinai , New York, NY, USA
                [6] 6Neuroscience Division, Douglas Mental Health University Institute, McGill University , Montreal, QC, Canada
                [7] 7The Agency for Science, Technology and Research, Singapore Institute for Clinical Sciences , Singapore
                Author notes

                Edited by: David M. Diamond, University of South Florida, USA

                Reviewed by: Klaus Peter Lesch, Universitätsklinikum Würzburg, Germany; Tania L. Roth, University of Delaware, USA

                *Correspondence: Rachel Yehuda, Traumatic Stress Studies Division, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, James J. Peters Veterans Affairs Medical Center, 526 OOMH PTSD 116/A, 130 West Kingsbridge Road, Bronx, NY 10468, USA e-mail: rachel.yehuda@ 123456va.gov

                This article was submitted to Molecular Psychiatry, a section of the journal Frontiers in Psychiatry.

                Article
                10.3389/fpsyt.2013.00118
                3784793
                24098286
                012fd1d0-0914-4f41-99a3-53604dd7b1ec
                Copyright © 2013 Yehuda, Daskalakis, Desarnaud, Makotkine, Lehrner, Koch, Flory, Buxbaum, Meaney and Bierer.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 01 June 2013
                : 11 September 2013
                Page count
                Figures: 9, Tables: 2, Equations: 0, References: 58, Pages: 14, Words: 9437
                Categories
                Psychiatry
                Original Research

                Clinical Psychology & Psychiatry
                ptsd,veterans,epigenetics,methylation,promoter,glucocorticoid receptor,fk506 binding protein 5,psychotherapy

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