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 Nemeroff, Florian Holsboer, Christine M. Heim, Kerry J. Ressler, Theo Rein, Elisabeth B. Binder

Research output: Contribution to journalArticle

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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
Pages (from-to)33-41
Number of pages9
JournalNature Neuroscience
Volume16
Issue number1
DOIs
StatePublished - Jan 1 2013

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Psychiatry
Alleles
Hormones
Transcription Initiation Site
DNA
Environmental Exposure
Wounds and Injuries
Brain
Response Elements
Human Development
Regulator Genes
Genetic Predisposition to Disease
Glucocorticoids
Genes
Chromatin
Genotype
tacrolimus binding protein 5

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Klengel, T., Mehta, D., Anacker, C., Rex-Haffner, M., Pruessner, J. C., Pariante, C. M., ... 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

Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. / Klengel, Torsten; Mehta, Divya; Anacker, Christoph; Rex-Haffner, Monika; Pruessner, Jens C.; Pariante, Carmine M.; Pace, Thaddeus W W; Mercer, Kristina B.; Mayberg, Helen S.; Bradley, Bekh; Nemeroff, Charles; Holsboer, Florian; Heim, Christine M.; Ressler, Kerry J.; Rein, Theo; Binder, Elisabeth B.

In: Nature Neuroscience, Vol. 16, No. 1, 01.01.2013, p. 33-41.

Research output: Contribution to journalArticle

Klengel, T, Mehta, D, Anacker, C, Rex-Haffner, M, Pruessner, JC, Pariante, CM, Pace, TWW, Mercer, KB, Mayberg, HS, Bradley, B, Nemeroff, C, Holsboer, F, Heim, CM, Ressler, KJ, Rein, T & Binder, EB 2013, 'Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions', Nature Neuroscience, vol. 16, no. 1, pp. 33-41. https://doi.org/10.1038/nn.3275
Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM et al. Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nature Neuroscience. 2013 Jan 1;16(1):33-41. https://doi.org/10.1038/nn.3275
Klengel, Torsten ; Mehta, Divya ; Anacker, Christoph ; Rex-Haffner, Monika ; Pruessner, Jens C. ; Pariante, Carmine M. ; Pace, Thaddeus W W ; Mercer, Kristina B. ; Mayberg, Helen S. ; Bradley, Bekh ; Nemeroff, Charles ; Holsboer, Florian ; Heim, Christine M. ; Ressler, Kerry J. ; Rein, Theo ; Binder, Elisabeth B. / Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. In: Nature Neuroscience. 2013 ; Vol. 16, No. 1. pp. 33-41.
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