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, K. Schuebel, A. Roy, D. Goldman

Research output: Contribution to journalArticlepeer-review

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

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Neurology
  • Behavioral Neuroscience

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