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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.

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Figure 1: FKBP5 × childhood abuse interaction on PTSD lifetime diagnosis.
Figure 2: Genotype- and glucocorticoid receptor–dependent enhancer activities of intron 2 sequences of FKBP5.
Figure 3: Long-distance interaction of GREs in FKBP5. Chromatin conformation capture confirmed a genotype-dependent interaction of the FKBP5 TSS (TSS) with intron 2 and intron 7 in lymphoblastoid cell lines.
Figure 4: DNA methylation of the FKBP5 locus.
Figure 5: Differential FKBP5 intron 7 DNA methylation depends on genotype and trauma exposure.
Figure 6: Effects of glucocorticoid receptor agonist treatment on FKBP5 DNA methylation in hippocampal progenitor cells.
Figure 7: Functional effects of FKBP5 intron 7 methylation.

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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).

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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.

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Correspondence to Torsten Klengel or Elisabeth B Binder.

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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).

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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

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