The influence of FKBP5 genotype on expression of FKBP5 and other glucocorticoid-regulated genes, dependent on trauma exposure

S. Yeo, M. A. Enoch, E. Gorodetsky, L. Akhtar, Kornel Schuebel, A. Roy, D. Goldman

Research output: Contribution to journalArticle

Abstract

The FK506 binding protein 51 (FKBP5), an intrinsic regulator of the glucocorticoid receptor, has been associated with pathological behaviors particularly in the context of childhood trauma (CT), via a putatively regulatory polymorphism, rs1360780. However, trans- and cis-acting effects of this locus and its interaction with CT are incompletely understood. To study its effects on the expression of glucocorticoid-regulated genes including FKBP5, we used lymphoblastoid cell lines (LCLs) derived from 16 CT-exposed patients with greater than two substance dependence/suicidal behavior diagnoses (casesCT+) and 13 non-CT-exposed controls (controlsCT−). This study in LCLs measures long-term trait-like differences attributable to genotype or lasting epigenetic modification. Through analysis of differential allelic expression (DAE) using an FKBP5 3′-UTR reporter single nucleotide polymorphism (SNP), rs3800373, that is in strong linkage disequilibrium with rs1360780, we confirmed that the rs1360780 risk allele (A) (or conceivably that of a linked SNP) leads to higher FKBP5 expression in controlsCT−. Intriguingly, casesCT+ did not show DAE, perhaps because of a genotype-predicted difference in FKBP5 DNA methylation restricted to casesCT+. Furthermore, through correlation analyses on FKBP5 expression at baseline and after induction by dexamethasone, we observed that casesCT+ had lower induction of FKBP5 expression, indicating that overall they may have strong ultra-short negative-feedback. Only casesCT+ showed an effect of rs1360780 genotype on expression of FKBP5 and other glucocorticoid-regulated genes. Together, these results confirm that the rs1360780 locus alters FKBP5 expression and further that in trans-fashion this locus affects the expression of other glucocorticoid-regulated genes after a glucocorticoid challenge. The CT exposure appears to be essential for trans-effects of rs1360780 on glucocorticoid-regulated genes.

Original languageEnglish (US)
Pages (from-to)223-232
Number of pages10
JournalGenes, Brain and Behavior
Volume16
Issue number2
DOIs
StatePublished - Feb 1 2017
Externally publishedYes

Fingerprint

Tacrolimus Binding Proteins
Glucocorticoids
Genotype
Wounds and Injuries
Genes
Single Nucleotide Polymorphism
Cell Line
Glucocorticoid Receptors
Linkage Disequilibrium
3' Untranslated Regions
DNA Methylation
Epigenomics
Dexamethasone
Substance-Related Disorders
Alleles

Keywords

  • cis-Acting regulation
  • differential allelic expression
  • DNA methylation
  • FKBP5
  • glucocorticoid
  • glucocorticoid receptor
  • rs1360780
  • trans-acting effect
  • trauma
  • ultra-short negative-feedback

ASJC Scopus subject areas

  • Genetics
  • Neurology
  • Behavioral Neuroscience

Cite this

The influence of FKBP5 genotype on expression of FKBP5 and other glucocorticoid-regulated genes, dependent on trauma exposure. / Yeo, S.; Enoch, M. A.; Gorodetsky, E.; Akhtar, L.; Schuebel, Kornel; Roy, A.; Goldman, D.

In: Genes, Brain and Behavior, Vol. 16, No. 2, 01.02.2017, p. 223-232.

Research output: Contribution to journalArticle

Yeo, S. ; Enoch, M. A. ; Gorodetsky, E. ; Akhtar, L. ; Schuebel, Kornel ; Roy, A. ; Goldman, D. / The influence of FKBP5 genotype on expression of FKBP5 and other glucocorticoid-regulated genes, dependent on trauma exposure. In: Genes, Brain and Behavior. 2017 ; Vol. 16, No. 2. pp. 223-232.
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AU - Goldman, D.

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AB - The FK506 binding protein 51 (FKBP5), an intrinsic regulator of the glucocorticoid receptor, has been associated with pathological behaviors particularly in the context of childhood trauma (CT), via a putatively regulatory polymorphism, rs1360780. However, trans- and cis-acting effects of this locus and its interaction with CT are incompletely understood. To study its effects on the expression of glucocorticoid-regulated genes including FKBP5, we used lymphoblastoid cell lines (LCLs) derived from 16 CT-exposed patients with greater than two substance dependence/suicidal behavior diagnoses (casesCT+) and 13 non-CT-exposed controls (controlsCT−). This study in LCLs measures long-term trait-like differences attributable to genotype or lasting epigenetic modification. Through analysis of differential allelic expression (DAE) using an FKBP5 3′-UTR reporter single nucleotide polymorphism (SNP), rs3800373, that is in strong linkage disequilibrium with rs1360780, we confirmed that the rs1360780 risk allele (A) (or conceivably that of a linked SNP) leads to higher FKBP5 expression in controlsCT−. Intriguingly, casesCT+ did not show DAE, perhaps because of a genotype-predicted difference in FKBP5 DNA methylation restricted to casesCT+. Furthermore, through correlation analyses on FKBP5 expression at baseline and after induction by dexamethasone, we observed that casesCT+ had lower induction of FKBP5 expression, indicating that overall they may have strong ultra-short negative-feedback. Only casesCT+ showed an effect of rs1360780 genotype on expression of FKBP5 and other glucocorticoid-regulated genes. Together, these results confirm that the rs1360780 locus alters FKBP5 expression and further that in trans-fashion this locus affects the expression of other glucocorticoid-regulated genes after a glucocorticoid challenge. The CT exposure appears to be essential for trans-effects of rs1360780 on glucocorticoid-regulated genes.

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