Identification of dynamic glucocorticoid-induced methylation changes at the FKBP5 locus

• Type of Material: Article
• Authors: Tobias Wiechmann, Max Planck Institute of Psychiatry; Simone Roeh, Max Planck Institute of Psychiatry; Susann Sauer, Max Planck Institute of Psychiatry; Darina Czamara, Max Planck Institute of Psychiatry; Janine Arloth, Max Planck Institute of Psychiatry; Maik Koedel, Max Planck Institute of Psychiatry; Madita Beintner, Max Planck Institute of Psychiatry; Lisanne Knop, Max Planck Institute of Psychiatry; Andreas Menke, University Hospital of Wuerzburg; Elisabeth B. Binder, Emory University; Nadine Provencal, Max Planck Institute of Psychiatry
• Language: English
• Date: 2019-05-23
• Publisher: BMC (part of Springer Nature)
• Publication Version: Final Published Version
• Copyright Statement: © 2019 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s13148-019-0682-5
• Title of Journal or Parent Work: Clinical Epigenetics
• ISSN: 1868-7075
• Volume: 11
• Issue: 1
• Start Page: 83
• End Page: 83
• Grant/Funding Information: This study was funded by the BMBF grant Berlin-LCS (FKZ 01KR1301B) to EBB and an ERC starting grant (GxE molmech, grant # 281338) within the FP7 funding scheme of the EU to EBB.; NP was funded by a research fellowship from the Canadian Institute of Health Research (CIHR).
• Keywords: Genetics & Heredity; LIFE EVENTS; Dexamethasone; Science & Technology; Oncology; Life Sciences & Biomedicine; BINDING; DNA METHYLATION; FKBP5; GENE; Targeted bisulfite sequencing; CHILDHOOD ADVERSITY; Early-life stress; RECEPTOR; DEXAMETHASONE; EXPRESSION; CTCF; Glucocorticoid receptor; DNA methylation; STRESS
• Research Categories: Psychology, Physiological; Health Sciences, Oncology; Biology, Genetics

Abstract

Background: Epigenetic mechanisms may play a major role in the biological embedding of early-life stress (ELS). One proposed mechanism is that glucocorticoid (GC) release following ELS exposure induces long-lasting alterations in DNA methylation (DNAm) of important regulatory genes of the stress response. Here, we investigate the dynamics of GC-dependent methylation changes in key regulatory regions of the FKBP5 locus in which ELS-associated DNAm changes have been reported. Results: We repeatedly measured DNAm in human peripheral blood samples from 2 independent cohorts exposed to the GC agonist dexamethasone (DEX) using a targeted bisulfite sequencing approach, complemented by data from Illumina 450K arrays. We detected differentially methylated CpGs in enhancers co-localizing with GC receptor binding sites after acute DEX treatment (1 h, 3 h, 6 h), which returned to baseline levels within 23 h. These changes withstood correction for immune cell count differences. While we observed main effects of sex, age, body mass index, smoking, and depression symptoms on FKBP5 methylation levels, only the functional FKBP5 SNP (rs1360780) moderated the dynamic changes following DEX. This genotype effect was observed in both cohorts and included sites previously shown to be associated with ELS. Conclusion: Our study highlights that DNAm levels within regulatory regions of the FKBP5 locus show dynamic changes following a GC challenge and suggest that factors influencing the dynamics of this regulation may contribute to the previously reported alterations in DNAm associated with current and past ELS exposure.