Alterations in DNA methylation of Fkbp5 as a determinant of blood-brain correlation of glucocorticoid exposure

Background: Epigenetic studies that utilize peripheral tissues to identify molecular substrates of neuropsychiatric disorders rely on the assumption that disease-relevant, cellular alterations that occur in the brain are mirrored and detectable in peripheral tissues such as blood. We sought to test this assumption by using a mouse model of Cushing's disease and asking whether epigenetic changes induced by glucocorticoids can be correlated between these tissue types.

Methods: Mice were treated with different doses of glucocorticoids in their drinking water for four weeks to assess gene expression and DNA methylation (DNAm) changes in the stress response gene Fkbp5.

Results: Significant linear relationships were observed between DNAm and four-week mean plasma corticosterone levels for both blood (R(2)=0.68, P=7.1×10(-10)) and brain (R(2)=0.33, P=0.001). Further, degree of methylation change in blood correlated significantly with both methylation (R(2)=0.49, P=2.7×10(-5)) and expression (R(2)=0.43, P=3.5×10(-5)) changes in hippocampus, with the notable observation that methylation changes occurred at different intronic regions between blood and brain tissues.

Conclusion: Although our findings are limited to several intronic CpGs in a single gene, our results demonstrate that DNA from blood can be used to assess dynamic, glucocorticoid-induced changes occurring in the brain. However, for such correlation analyses to be effective, tissue-specific locations of these epigenetic changes may need to be considered when investigating brain-relevant changes in peripheral tissues.