DNA methylation patterns of FKBP5 regulatory regions in brain and blood of humanized mice and humans

Abstract

Humanized mouse models can be used to explore human gene regulatory elements (REs), which frequently lie in non-coding and less conserved genomic regions. Epigenetic modifications of gene REs, also in the context of gene x environment interactions, have not yet been explored in humanized mouse models. We applied high-accuracy measurement of DNA methylation (DNAm) via targeted bisulfite sequencing (HAM-TBS) to investigate DNAm in three tissues/brain regions (blood, prefrontal cortex and hippocampus) of mice carrying the human FK506-binding protein 5 (FKBP5) gene, an important candidate gene associated with stress-related psychiatric disorders. We explored DNAm in three functional intronic glucocorticoid-responsive elements (at introns 2, 5, and 7) of FKBP5 at baseline, in cases of differing genotype (rs1360780 single nucleotide polymorphism), and following application of the synthetic glucocorticoid dexamethasone. We compared DNAm patterns in the humanized mouse (N = 58) to those in human peripheral blood (N = 447 and N = 89) and human postmortem brain prefrontal cortex (N = 86). Overall, DNAm patterns in the humanized mouse model seem to recapitulate DNAm patterns observed in human tissue. At baseline, this was to a higher extent in brain tissue. The animal model also recapitulated effects of dexamethasone on DNAm, especially in peripheral blood and to a lesser extent effects of genotype on DNAm. The humanized mouse model could thus assist in reverse translation of human findings in psychiatry that involve genetic and epigenetic regulation in non-coding elements.

The Role of FKBPs in Complex Disorders: Neuropsychiatric Diseases, Cancer, and Type 2 Diabetes Mellitus

“…Studies on FKBP5 knockout mice and inhibition of FKBP51 suggest that inhibiting FKBP51 could alleviate depressive symptoms without affecting cognition or movement [97,98]. FKBP5 methylation in mice correlates positively with chronic stress in the blood and brain [99,100]. Human studies indicate elevated FKBP51 levels in the lymphocytes of depressed individuals with common FKBP5 gene variations, associated with a quicker response to antidepressants but more frequent depressive episodes [101].…”