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 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 EPIGENETIC DIFFERENCES IN STRESS RESPONSE GENE _FKBP5_ AMONG CHILDREN WITH ABUSIVE VS ACCIDENTAL INJURIES Article 09 January

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  Google Scholar  Download 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 author publications You can also search for this author inPubMed Google Scholar * Monika Rex-Haffner View author publications You can also search for this author

inPubMed Google Scholar * Jens C Pruessner View author publications You can also search for this author inPubMed Google Scholar * Carmine M Pariante View author publications You can also

search for this author inPubMed Google Scholar * Thaddeus W W Pace View author publications You can also search for this author inPubMed Google Scholar * Kristina B Mercer View author

publications You can also search for this author inPubMed Google Scholar * Helen S Mayberg View author publications You can also search for this author inPubMed Google Scholar * Bekh Bradley

View author publications You can also search for this author inPubMed Google Scholar * Charles B Nemeroff View author publications You can also search for this author inPubMed Google

Scholar * Florian Holsboer View 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

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