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Journal Article

Chaperoning epigenetics: FKBP51 decreases the activity of DNMT1 and mediates epigenetic effects of the antidepressant paroxetine.

MPS-Authors
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Gassen,  Nils C.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Fries,  Gabriel R.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Zannas,  Anthony S.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Zschocke,  Jürgen
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Hafner,  Kathrin
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Carrillo-Roa,  Tania
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Preißinger,  S. Nicole
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Hoeijmakers,  Lianne
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

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Knop,  Matthias
Dept. Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society;

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Weber,  Frank
Dept. Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society;

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Kloiber,  Stefan
Dept. Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society;

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Lucae,  Susanne
Dept. Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society;

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Ising,  Marcus
Dept. Clinical Research, Max Planck Institute of Psychiatry, Max Planck Society;

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Binder,  Elisabeth B.
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Schmidt,  Mathias V.
Dept. Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Max Planck Society;

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Rein,  Theo
Dept. Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Max Planck Society;

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Citation

Gassen, N. C., Fries, G. R., Zannas, A. S., Hartmann, J., Zschocke, J., Hafner, K., et al. (2015). Chaperoning epigenetics: FKBP51 decreases the activity of DNMT1 and mediates epigenetic effects of the antidepressant paroxetine. Science signaling, 8(404), ra119-ra119. doi:10.1126/scisignal.aac7695.


Cite as: https://hdl.handle.net/11858/00-001M-0000-002A-0426-9
Abstract
Epigenetic processes, such as DNA methylation, and molecular chaperones, including FK506-binding protein 51 (FKBP51), are independently implicated in stress-related mental disorders and antidepressant drug action. FKBP51 associates with cyclin-dependent kinase 5 (CDK5), which is one of several kinases that phosphorylates and activates DNA methyltransferase 1 (DNMT1). We searched for a functional link between FKBP51 (encoded by FKBP5) and DNMT1 in cells from mice and humans, including those from depressed patients, and found that FKBP51 competed with its close homolog FKBP52 for association with CDK5. In human embryonic kidney (HEK) 293 cells, expression of FKBP51 displaced FKBP52 from CDK5, decreased the interaction of CDK5 with DNMT1, reduced the phosphorylation and enzymatic activity of DNMT1, and diminished global DNA methylation. In mouse embryonic fibroblasts and primary mouse astrocytes, FKBP51 mediated several effects of paroxetine, namely, decreased the protein-protein interactions of DNMT1 with CDK5 and FKBP52, reduced phosphorylation of DNMT1, and decreased the methylation and increased the expression of the gene encoding brain-derived neurotrophic factor (Bdnf). In human peripheral blood cells, FKBP5 expression inversely correlated with both global and BDNF methylation. Peripheral blood cells isolated from depressed patients that were then treated ex vivo with paroxetine revealed that the abundance of BDNF positively correlated and phosphorylated DNMT1 inversely correlated with that of FKBP51 in cells and with clinical treatment success in patients, supporting the relevance of this FKBP51-directed pathway that prevents epigenetic suppression of gene expression.