Johns Hopkins Mood Disorders Center

Baltimore, MD, United States

Johns Hopkins Mood Disorders Center

Baltimore, MD, United States

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Ewald E.R.,Johns Hopkins Mood Disorders Center | Seifuddin F.,Johns Hopkins Mood Disorders Center | Tamashiro K.L.,Johns Hopkins Mood Disorders Center | Potash J.B.,University of Iowa | And 3 more authors.
Psychoneuroendocrinology | Year: 2014

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 (R2=0.68, P=7.1×10-10) and brain (R2=0.33, P=0.001). Further, degree of methylation change in blood correlated significantly with both methylation (R2=0.49, P=2.7×10-5) and expression (R2=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. © 2014 Elsevier Ltd.


PubMed | Johns Hopkins University, Johns Hopkins Mood Disorders Center and University of Iowa
Type: | Journal: Psychoneuroendocrinology | Year: 2014

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 Cushings disease and asking whether epigenetic changes induced by glucocorticoids can be correlated between these tissue types.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.Significant linear relationships were observed between DNAm and four-week mean plasma corticosterone levels for both blood (R(2)=0.68, P=7.110(-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=2.710(-5)) and expression (R(2)=0.43, P=3.510(-5)) changes in hippocampus, with the notable observation that methylation changes occurred at different intronic regions between blood and brain tissues.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.


Lee R.S.,Johns Hopkins Mood Disorders Center | Pirooznia M.,Johns Hopkins Mood Disorders Center | Guintivano J.,Johns Hopkins Mood Disorders Center | Guintivano J.,University of Maryland, Baltimore | And 6 more authors.
Translational Psychiatry | Year: 2015

Epigenetics may have an important role in mood stabilizer action. Valproic acid (VPA) is a histone deacetylase inhibitor, and lithium (Li) may have downstream epigenetic actions. To identify genes commonly affected by both mood stabilizers and to assess potential epigenetic mechanisms that may be involved in their mechanism of action, we administered Li (N = 12), VPA (N = 12), and normal chow (N = 12) to Brown Norway rats for 30 days. Genomic DNA and mRNA were extracted from the hippocampus. We used the mRNA to perform gene expression analysis on Affymetrix microarray chips, and for genes commonly regulated by both Li and VPA, we validated expression levels using quantitative real-time PCR. To identify potential mechanisms underlying expression changes, genomic DNA was bisulfite treated for pyrosequencing of key CpG island 'shores' and promoter regions, and chromatin was prepared from both hippocampal tissue and a hippocampal-derived cell line to assess modifications of histones. For most genes, we found little evidence of DNA methylation changes in response to the medications. However, we detected histone H3 methylation and acetylation in the leptin receptor gene, Lepr, following treatment with both drugs. VPA-mediated effects on histones are well established, whereas the Li effects constitute a novel mechanism of transcriptional derepression for this drug. These data support several shared transcriptional targets of Li and VPA, and provide evidence suggesting leptin signaling as an epigenetic target of two mood stabilizers. Additional work could help clarify whether leptin signaling in the brain has a role in the therapeutic action of Li and VPA in bipolar disorder.

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