Fkbp5 allele-specific epigenetic modification in gene by environment interaction

The likelihood to develop stress-related psychiatric disorders in response to childhood trauma exposure may be moderated by the individual’s genetic predisposition (Manuck and McCaffery,

2014). One of the genetic variants reported to alter the risk for psychiatric disorders following childhood trauma is a functional variant in _FKBP5_, a gene encoding a co-chaperone of the

glucocorticoid receptor (GR). _FKBP5_ is strongly induced following stress exposure via binding of activated GR to a number of intronic and promoter GR response elements (GREs). The protein

itself then binds to the GR complex, reduces the affinity of GR to cortisol and decreases translocation of the GR to the nucleus, providing an ultrashort negative feedback for GR activation

on the genomic and protein level (Zannas and Binder, 2014). We have identified a functional polymorphism in close proximity of a GRE in intron 2 of _FKBP5_, which alters the extent of mRNA

and protein induction following GR activation, likely by an altered 3D conformation. This results in a variable interaction of the intron 2 GRE with the transcription start site, leading to

increased or reduced mRNA induction, respectively (Klengel et al, 2013). Individuals carrying the allele associated with stronger _FKBP5_ mRNA induction show GR resistance, prolonged

cortisol response following stress, altered activation of brain regions important for threat response, such as the amygdala, and increased risk to a number of psychiatric disorders including

major depression and post-traumatic stress disorder when exposed to childhood trauma. Interestingly, while the genetic effects on the physiological stress response are seen in adults, no

interaction of adult trauma with this genotype on psychiatric risk is observed, suggesting an additional mechanism that explains the _FKBP5_ × childhood trauma interaction. In fact, we could

show that exposure to childhood trauma leads to allele-specific epigenetic changes with a decrease in DNA methylation in a second GRE located in intron 7 of the gene, but only in carriers

of the risk allele. This demethylation further de-represses _FKBP5_ induction following GR exposure and is likely mediated by the genetically determined increase in cortisol response

following stress (Klengel et al, 2013) (Figure 1). Indeed, direct GR activation with a selective agonist in a neuronal progenitor cell line leads to a demethylation in exactly the same CG

dinucleotides (CpGs) that are shown to be less methylated in DNA from peripheral blood in trauma-exposed risk allele carriers. These CpGs are located either within or between GR consensus

binding site sequences, while more proximal CpGs are unaffected. We thus speculate that the demethylation is an active demethylation, induced by GR binding. Such active demethylation at GREs

has been described before (Kress et al, 2006) and, although not directly shown, hydroxymethylation could be an intermediate step in this active transcription factor binding-induced

demethylation (Bhutani et al, 2011), a process that has been described for other transcription factors as well (Feldmann et al, 2013). On a more general level, any genetic variant that

alters binding of stress-induced transcription factors may thus lead to local differences in subsequent epigenetic changes. Thereby, allele-specific epigenetic modifications can contribute

to gene × environment interactions, leading to long-term effects of stress on endocrine levels, brain activity, and the risk to develop psychiatric disorders. FUNDING AND DISCLOSURE Funding

for the research presented here was provided by the European Research Council grant no. 281338, the National Institute of Mental Health grants (MH071538 and MH58922), the Max Planck Society,

and the Behrens Weise Stiftung. TK is supported by an EMBO long-term fellowship (ALTF 1153-2013). EBB is holding a patent for the use of FKBP5 in antidepressant therapy (WO 2005/054500:

FKBP5: a novel target for antidepressant therapy) and received an honorarium from GSK. REFERENCES * Bhutani N, Burns DM, Blau HM (2011). DNA demethylation dynamics. _Cell_ 146: 866–872.

Article  CAS  Google Scholar  * Feldmann A, Ivanek R, Murr R, Gaidatzis D, Burger L, Schuebeler D (2013). Transcription factor occupancy can mediate active turnover of DNA methylation at

regulatory regions. _PLoS Genet_ 9: e1003994. Article  Google Scholar  * Klengel T, Mehta D, Anacker C, Rex-Haffner M, Pruessner JC, Pariante CM _et al_ (2013). Allele-specific FKBP5 DNA

demethylation mediates gene-childhood trauma interactions. _Nat Neurosci_ 16: 33–41. Article  CAS  Google Scholar  * Kress C, Thomassin H, Grange T (2006). Active cytosine demethylation

triggered by a nuclear receptor involves DNA strand breaks. _Proc Natl Acad Sci USA_ 103: 11112–11117. Article  CAS  Google Scholar  * Manuck SB, McCaffery JM (2014). Gene-environment

interaction. In: Fiske ST, (ed). _Annual Review of Psychology_, VOL 65. Annual Reviews: Palo Alto, CA. pp 41–70. Google Scholar  * Zannas AS, Binder EB (2014). Gene-environment interactions

at the FKBP5 locus: sensitive periods, mechanisms and pleiotropism. _Genes Brain Behav_ 13: 25–37. Article  CAS  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, Germany Torsten Klengel & Elisabeth B Binder * Department of Psychiatry and

Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, USA Torsten Klengel & Elisabeth B Binder Authors * Torsten Klengel 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 CORRESPONDING AUTHOR Correspondence to

Elisabeth B Binder. POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Klengel, T., Binder, E. _FKBP5_

Allele-Specific Epigenetic Modification in Gene by Environment Interaction. _Neuropsychopharmacol_ 40, 244–246 (2015). https://doi.org/10.1038/npp.2014.208 Download citation * Published: 08

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