Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-kappa B-driven inflammation and cardiovascular risk

• Type of Material: Article
• Authors: Anthony S. Zannas, Max Planck Institute of Psychiatry; Meiwen Jia, Max Planck Institute of Psychiatry; Kathrin Hafner, Max Planck Institute of Psychiatry; Jens Baumert, German Research Center for Environmental Health; Tobias Wiechmann, Max Planck Institute of Psychiatry; Julius C. Pape, Max Planck Institute of Psychiatry; Janine Arloth, Max Planck Institute of Psychiatry; Maik Koedel, Max Planck Institute of Psychiatry; Silvia Martinelli, Max Planck Institute of Psychiatry; Maria Roitman, Max Planck Institute of Psychiatry; Simone Roeh, Max Planck Institute of Psychiatry; Andreas Haehle, Technische Universität Darmstadt; Rebecca T. Emeny, Dartmouth College; Stella Iurato, Max Planck Institute of Psychiatry; Tania Carrillo-Roa, Max Planck Institute of Psychiatry; Jari Lahti, University of Helsinki; Katri Raikkonen, University of Helsinki; Johan G. Eriksson, University of Helsinki; Amanda J. Drake, University of Edinburgh; Melanie Waldenberger, German Research Center for Environmental Health; Simone Wahl, German Research Center for Environmental Health; Sonja Kunze, German Research Center for Environmental Health; Susanne Lucae, Max Planck Institute of Psychiatry; Bekh Bradley-Davino, Emory University; Christian Gieger, German Research Center for Environmental Health; Felix Hausch, Technische Universität Darmstadt; Alicia K Smith, Emory University; Kerry Ressler, Emory University; Bertram Mueller-Myhsok, Max Planck Institute of Psychiatry; Karl-Heinz Ladwig, German Research Center for Environmental Health; Theo Rein, Max Planck Institute of Psychiatry; Nils C. Gassen, Max Planck Institute of Psychiatry; Elisabeth B. Binder, Emory University
• Language: English
• Date: 2019-06-04
• Publisher: National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2019 National Academy of Sciences. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1816847116
• Title of Journal or Parent Work: Proceedings of the National Academy of Sciences
• ISSN: 0027-8424
• Volume: 116
• Issue: 23
• Start Page: 11370
• End Page: 11379
• Grant/Funding Information: This work was supported by a Marie-Sklodowska Curie fellowship (H2020 Grant 653240) to A.S.Z., a grant from the National Institute of Mental Health (MH071538) to K.J.R., a European Research Council starting grant within the FP7 Framework to E.B.B. (Grant 281338, GxE molmech), a grant from the National Institute of Mental Health (U19 MH069056), a grant by the German Federal Ministry of Education and Research (BMBF) through the Integrated Network IntegraMent (Integrated Understanding of Causes and Mechanisms in Mental Disorders) under the auspices of the e:Med Programme (Grant 01ZX1314J) to E.B.B., and by the Academy of Finland (Grants 284859, 2848591, and 312670).
• Keywords: epigenetics; Multidisciplinary Sciences; FKBP5; ALL-CAUSE MORTALITY; HEALTHY-MEN; HEART; DISEASE; Science & Technology; ADVERSE CHILDHOOD EXPERIENCES; psychosocial stress; DEPRESSIVE SYMPTOMS; IL-8; C-REACTIVE PROTEIN; DNA METHYLATION; aging; LYMPHOCYTE RATIO; inflammation; Science & Technology - Other Topics
• Research Categories: Biology, Genetics; Psychology, Behavioral; Health Sciences, Medicine and Surgery

Abstract

Aging and psychosocial stress are associated with increased inflammation and disease risk, but the underlying molecular mechanisms are unclear. Because both aging and stress are also associated with lasting epigenetic changes, a plausible hypothesis is that stress along the lifespan could confer disease risk through epigenetic effects on molecules involved in inflammatory processes. Here, by combining large-scale analyses in human cohorts with experiments in cells, we report that FKBP5, a protein implicated in stress physiology, contributes to these relations. Across independent human cohorts (total n > 3,000), aging synergized with stress-related phenotypes, measured with childhood trauma and major depression questionnaires, to epigenetically up-regulate FKBP5 expression. These age/ stress-related epigenetic effects were recapitulated in a cellular model of replicative senescence, whereby we exposed replicating human fibroblasts to stress (glucocorticoid) hormones. Unbiased genome-wide analyses in human blood linked higher FKBP5 mRNA with a proinflammatory profile and altered NF-κB-related gene networks. Accordingly, experiments in immune cells showed that higher FKBP5 promotes inflammation by strengthening the interactions of NF-κB regulatory kinases, whereas opposing FKBP5 either by genetic deletion (CRISPR/Cas9-mediated) or selective pharmacological inhibition prevented the effects on NF-κB. Further, the age/stress-related epigenetic signature enhanced FKBP5 response to NF-κB through a positive feedback loop and was present in individuals with a history of acute myocardial infarction, a disease state linked to peripheral inflammation. These findings suggest that aging/stressdriven FKBP5-NF-κB signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.