Allele-specific fkbp5 dna demethylation mediates gene–childhood trauma interactions

ABSTRACT 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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS

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institutional subscriptions * Read our FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS NO ASSOCIATION BETWEEN _FKBP5_ GENE METHYLATION AND ACUTE AND LONG-TERM CORTISOL

OUTPUT Article Open access 02 June 2020 DISSECTING EARLY LIFE STRESS-INDUCED ADOLESCENT DEPRESSION THROUGH EPIGENOMIC APPROACH Article Open access 14 December 2022 LOW LEVELS OF _METHYL-CPG

BINDING PROTEIN 2_ ARE ACCOMPANIED BY AN INCREASED VULNERABILITY TO THE NEGATIVE OUTCOMES OF STRESS EXPOSURE DURING CHILDHOOD IN HEALTHY WOMEN Article Open access 08 December 2022 ACCESSION

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references ACKNOWLEDGEMENTS We thank T. Mletzko, K. Hafner and N.C. Gassen for their help in acquiring and interpreting data, and P. Weber for data visualization. Special thanks to A.W.

Graham, A. Brown, D. Crain and D. Cross for their assistance in recruiting subjects and managing the Grady Trauma Project. This work was supported by a European Research Council starting

grant (grant #281338, GxE molmech), a grant from the National Alliance for Research in Schizophrenia and Affective Disorders and a grant from the Behrens Weise Stiftung to E.B.B., a grant

from the National Institute of Mental Health (MH071538) to K.J.R., and a grant from the National Institute of Mental Health (MH58922) to C.B.N., C.M.P. and C.A. have received funding from

the National Institute for Health Research Biomedical Research Centre for Mental Health, Institute of Psychiatry and South London and Maudsley National Health System Foundation Trust, a

Clinician Scientist Fellowship from the UK Medical Research Council (G108/603) to C.M.P., and the Commission of European Communities 7th Framework Programme Collaborative Project Grant

Agreement n 22963 (Mood Inflame), also to C.M.P., C.M.H. is supported in part by Public Health Service Grant UL1 RR025008 from the Clinical and Translational Science Award program, the US

National Institutes of Health, the National Center for Research Resources and by a K Award (K01 MH073698–01, Neural Substrates of Depression Risk after Child Abuse). AUTHOR INFORMATION

AUTHORS AND AFFILIATIONS * Max Planck Institute of Psychiatry, Munich, Germany Torsten Klengel, Divya Mehta, Monika Rex-Haffner, Florian Holsboer, Theo Rein & Elisabeth B Binder *

Department of Psychological Medicine, King's College London, Institute of Psychiatry, Section of Perinatal Psychiatry and Stress, Psychiatry and Immunology, London, UK Christoph Anacker

 & Carmine M Pariante * McGill Centre for Studies in Aging, Faculty of Medicine, McGill University, Verdun, Quebec, Canada Jens C Pruessner * Department of Psychiatry and Behavioral

Sciences, Emory University School of Medicine, Atlanta, Georgia, USA Thaddeus W W Pace, Helen S Mayberg, Bekh Bradley, Christine M Heim, Kerry J Ressler & Elisabeth B Binder * Howard

Hughes Medical Institute, Chevy Chase, Maryland, USA Kristina B Mercer & Kerry J Ressler * Atlanta Veterans Affairs Medical Center, Decatur, Georgia, USA Bekh Bradley * Department of

Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, Florida, USA Charles B Nemeroff * Institute of Medical Psychology, Charité University Medicine

Berlin, Berlin, Germany Christine M Heim * Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA Kerry J Ressler Authors * Torsten Klengel View author publications

You can also search for this author inPubMed Google Scholar * Divya Mehta View author publications You can also search for this author inPubMed Google Scholar * Christoph Anacker View

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author publications You can also search for this author inPubMed Google Scholar * Christine M Heim View author publications You can also search for this author inPubMed Google Scholar *

Kerry J Ressler View author publications You can also search for this author inPubMed Google Scholar * Theo Rein View author publications You can also search for this author inPubMed Google

Scholar * Elisabeth B Binder View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS T.K. and E.B.B. designed the experiments, performed the

luciferase assays and the genetic, methylation and expression analyses, analyzed the data, and wrote the initial version of the paper. D.M. performed the RNA expression experiments and data

analyses and revised the paper. M.R.-H. performed the chromatin conformation capture experiments. C.A. and C.M.P. performed the cell-culture experiments with human hippocampal progenitor

cells and revised the paper. T.W.W.P. performed _ex vivo_ glucocorticoid receptor sensitivity experiments and revised the paper. J.C.P. analyzed magnetic resonance imaging data and revised

the paper. E.B.B., F.H., K.J.R., K.B.M., H.S.M., B.B., C.B.N., C.M.H. and T.R. organized sample collection and collaborations, obtained funding, supervised data analyses, and revised the

paper. CORRESPONDING AUTHORS Correspondence to Torsten Klengel or Elisabeth B Binder. ETHICS DECLARATIONS COMPETING INTERESTS E.B.B., T.R. and F.H. hold a patent for the use of FKBP5 in

antidepressant therapy (WO 2005/054500: FKBP5: a novel target for antidepressant therapy). SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Figures 1–7 and

Supplementary Tables 1–5 (PDF 293 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Klengel, T., Mehta, D., Anacker, C. _et al._ Allele-specific

_FKBP5_ DNA demethylation mediates gene–childhood trauma interactions. _Nat Neurosci_ 16, 33–41 (2013). https://doi.org/10.1038/nn.3275 Download citation * Received: 15 June 2012 * Accepted:

01 November 2012 * Published: 02 December 2012 * Issue Date: January 2013 * DOI: https://doi.org/10.1038/nn.3275 SHARE THIS ARTICLE Anyone you share the following link with will be able to

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