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

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/stress-driven FKBP5-NF-κB signaling mediates inflammation, potentially contributing to cardiovascular risk, and may thus point to novel biomarker and treatment possibilities.

• Authors: Anthony S Zannas, Meiwen Jia, Kathrin Hafner, Jens Baumert, Tobias Wiechmann, Julius C Pape, Janine Arloth, Maik Ködel, Silvia Martinelli, Maria Roitman, Simone Röh, Andreas Haehle, Rebecca T Emeny, Stella Iurato, Tania Carrillo-Roa, Jari Lahti, Katri Räikkönen, Johan G Eriksson, Amanda J Drake, Melanie Waldenberger, Simone Wahl, Sonja Kunze, Susanne Lucae, Bekh Bradley, Christian Gieger, Felix Hausch, Alicia K Smith, Kerry J Ressler, Bertram Müller-Myhsok, Karl-Heinz Ladwig, Theo Rein, Nils C Gassen, Elisabeth B Binder
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 116 Issue 23 Pg. 11370-11379 (06 04 2019) ISSN: 1091-6490 [Electronic] United States
• PMID: 31113877 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 the Author(s). Published by PNAS.

Chemical References

• NF-kappa B
• Tacrolimus Binding Proteins
• tacrolimus binding protein 5

Topics

• Aging (genetics)
• Cardiovascular Diseases (genetics)
• Cellular Senescence (genetics)
• Child, Preschool
• Depressive Disorder, Major (genetics)
• Epigenesis, Genetic (genetics)
• Female
• Genome-Wide Association Study (methods)
• Humans
• Inflammation (genetics)
• Male
• NF-kappa B (genetics)
• Risk Factors
• Signal Transduction (genetics)
• Stress, Psychological (genetics)
• Tacrolimus Binding Proteins (genetics)
• Up-Regulation (genetics)