title: Chaperoning epigenetics: FKBP51 decreases the activity of DNMT1 and mediates epigenetic effects of the antidepressant paroxetine.
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.
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany. ncgassen@psych.mpg.de theorein@psych.mpg.de.
authors.forename: Nils C
authors.initials: NC
authors.lastname: Gassen
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany. Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center, Houston, TX 77054, USA.
authors.forename: Gabriel R
authors.initials: GR
authors.lastname: Fries
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany. Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Anthony S
authors.initials: AS
authors.lastname: Zannas
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Hartmann
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Zschocke
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Hafner
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Tania
authors.initials: T
authors.lastname: Carrillo-Roa
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry and Pharmacy, Ludwig Maximilians University, 81377 Munich, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Steinbacher
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: S Nicole
authors.initials: SN
authors.lastname: Preißinger
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Lianne
authors.initials: L
authors.lastname: Hoeijmakers
authors.affiliation: Department of Clinical Research, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Knop
authors.affiliation: Department of Clinical Research, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Weber
authors.affiliation: Department of Clinical Research, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kloiber
authors.affiliation: Department of Clinical Research, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Lucae
authors.affiliation: First Department of Pediatrics, University of Athens Medical School, Athens 11527, Greece.
authors.forename: George P
authors.initials: GP
authors.lastname: Chrousos
authors.affiliation: Department of Organic Chemistry, Faculty of Chemistry and Pharmacy, Ludwig Maximilians University, 81377 Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Carell
authors.affiliation: Department of Clinical Research, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ising
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30329, USA.
authors.forename: Elisabeth B
authors.initials: EB
authors.lastname: Binder
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany.
authors.forename: Mathias V
authors.initials: MV
authors.lastname: Schmidt
authors.affiliation: Department of Clinical Neuroscience, Center for Molecular Medicine, Karolinska Institutet, 171 76 Stockholm, Sweden and Swedish Toxicology Science Research Center, Swetox, 151 36 Södertälje, Sweden.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Rüegg
authors.affiliation: Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany. ncgassen@psych.mpg.de theorein@psych.mpg.de.
authors.forename: Theo
authors.initials: T
authors.lastname: Rein
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation / Q000187:drug effects / Q000235:genetics; D003863:Depression / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D044127:Epigenesis, Genetic / Q000187:drug effects*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D017374:Paroxetine / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D022021:Tacrolimus Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000099159:Tacrolimus Binding Protein 5
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D017374:Paroxetine; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C579455:BDNF protein, human; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse