Alterations in DNA methylation of Fkbp5 as a determinant of blood–brain correlation of glucocorticoid exposure
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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.
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Some overlap exists between MDD-associated differentially methylated regions in blood and the MDD-associated DMRs in the prefrontal cortex and other brain regions.
“Previous work indicates some overlap between MDD-associated differentially methylated regions (DMRs) in blood and the MDD-associated DMRs in the prefrontal cortex and other brain regions.82–85”
From Epigenetic regulation in major depression and other stress-related disorders: molecular mechanisms, clinical relevance and therapeutic potential (2023) · cites this paper as [83]
The Results (§3.4; page unavailable) report a correlation between Fkbp5 methylation in mouse blood and hippocampus after glucocorticoid exposure. The Discussion (§4; page unavailable) also describes blood–brain methylation concordance in other settings. Neither passage establishes overlap between MDD-associated DMRs in blood and those in the prefrontal cortex or other brain regions. (LLM, conf=0.84)
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- Authors
- Ewald, E. R., Wand, G. S., Seifuddin, F., Yang, X., Tamashiro, K. L., Potash, J. B., Zandi, P., & Lee, R. S.
- Affiliations
- Johns Hopkins University (US)
- University of Iowa (US)
- Corresponding author
- Lee, Richard S.
- Venue
- Psychoneuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 44
- Pages
- 112-122
- ISSN
- 0306-4530 (ISSN-L)
- PMC
- PMC4047971
- OpenAlex
- W2117041810
- Cited by
- 105
- References
- 43
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 5 · 2023: 6 · 2022: 8 · 2021: 7 · 2020: 10 · 2019: 11 · 2018: 13 · 2017: 15 · 2016: 8 · 2015: 11 · 2014: 5
- FWCI
- 4.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Psychoneuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (UO1 AA020890, K05AA020342, U01AA020890)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD-055030, R00HD055030, K99HD055030)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Syndromes and Imprinting
- Keywords
- DNA methylation, FKBP5, glucocorticoids, Cushing's disease, epigenetic biomarkers, corticosterone, hippocampus
- MeSH terms
- Tacrolimus Binding Protein 5, Animals, Brain, Corticosterone, Glucocorticoids, Male, Mice, Inbred C57BL, DNA Methylation, Tacrolimus Binding Proteins, Mice
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