Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions

Torsten Klengel, Divya Mehta, Christoph Anacker, Monika Rex-Haffner, Jens C. Pruessner, Carmine M. Pariante, Thaddeus W.W. Pace, Kristina B. Mercer, Helen S. Mayberg, Bekh Bradley, Charles B. Nemeroff, Florian Holsboer, Christine M. Heim, Kerry J. Ressler, Theo Rein, Elisabeth B. Binder

Research output: Contribution to journalArticle

776 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)33-41
Number of pages9
JournalNature Neuroscience
Volume16
Issue number1
DOIs
StatePublished - Jan 2013

ASJC Scopus subject areas

  • Neuroscience(all)

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    Klengel, T., Mehta, D., Anacker, C., Rex-Haffner, M., Pruessner, J. C., Pariante, C. M., Pace, T. W. W., Mercer, K. B., Mayberg, H. S., Bradley, B., Nemeroff, C. B., Holsboer, F., Heim, C. M., Ressler, K. J., Rein, T., & Binder, E. B. (2013). Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nature Neuroscience, 16(1), 33-41. https://doi.org/10.1038/nn.3275