Identification of dynamic glucocorticoid-induced methylation changes at the FKBP5 locus.
Adult
Cohort Studies
DNA Methylation
/ drug effects
Dexamethasone
/ adverse effects
Epigenesis, Genetic
/ drug effects
Female
Glucocorticoids
/ agonists
Humans
Male
Middle Aged
Oligonucleotide Array Sequence Analysis
Polymorphism, Single Nucleotide
Regulatory Sequences, Nucleic Acid
Sequence Analysis, DNA
Stress, Psychological
/ genetics
Tacrolimus Binding Proteins
/ genetics
Young Adult
DNA methylation
Dexamethasone
Early-life stress
FKBP5
Glucocorticoid receptor
Targeted bisulfite sequencing
Journal
Clinical epigenetics
ISSN: 1868-7083
Titre abrégé: Clin Epigenetics
Pays: Germany
ID NLM: 101516977
Informations de publication
Date de publication:
23 05 2019
23 05 2019
Historique:
received:
27
11
2018
accepted:
09
05
2019
entrez:
25
5
2019
pubmed:
28
5
2019
medline:
27
5
2020
Statut:
epublish
Résumé
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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 31122292
doi: 10.1186/s13148-019-0682-5
pii: 10.1186/s13148-019-0682-5
pmc: PMC6533766
doi:
Substances chimiques
Glucocorticoids
0
Dexamethasone
7S5I7G3JQL
Tacrolimus Binding Proteins
EC 5.2.1.-
tacrolimus binding protein 5
EC 5.2.1.8
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
83Subventions
Organisme : European Research Council
ID : 281338
Pays : International
Organisme : CIHR
Pays : Canada
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