TY - JOUR
T1 - Genome-wide Methyl-Seq analysis of blood-brain targets of glucocorticoid exposure
AU - Seifuddin, Fayaz
AU - Wand, Gary
AU - Cox, Olivia
AU - Pirooznia, Mehdi
AU - Moody, Laura
AU - Yang, Xiaoju
AU - Tai, Jonathan
AU - Boersma, Gretha
AU - Tamashiro, Kellie
AU - Zandi, Peter
AU - Lee, Richard
N1 - Publisher Copyright:
© 2017 Taylor & Francis Group, LLC.
PY - 2017/8/3
Y1 - 2017/8/3
N2 - Chronic exposure to glucocorticoids (GCs) can lead to psychiatric complications through epigenetic mechanisms such as DNA methylation (DNAm). We sought to determine whether epigenetic changes in a peripheral tissue can serve as a surrogate for those in a relatively inaccessible tissue such as the brain. DNA extracted from the hippocampus and blood of mice treated with GCs or vehicle solution was assayed using a genome-wide DNAm platform (Methyl-Seq) to identify differentially methylated regions (DMRs) induced by GC treatment. We observed that ∼70% of the DMRs in both tissues lost methylation following GC treatment. Of the 3,095 DMRs that mapped to the same genes in both tissues, 1,853 DMRs underwent DNAm changes in the same direction. Interestingly, only 209 DMRs (<7%) overlapped in genomic coordinates between the 2 tissues, suggesting tissue-specific differences in GC-targeted loci. Pathway analysis showed that the DMR-associated genes were members of pathways involved in metabolism, immune function, and neurodevelopment. Also, changes in cell type composition of blood and brain were examined by fluorescence-activated cell sorting. Separation of the cortex into neuronal and non-neuronal fractions and the leukocytes into T-cells, B-cells, and neutrophils showed that GC-induced methylation changes primarily occurred in neurons and T-cells, with the blood tissue also undergoing a shift in the proportion of constituent cell types while the proportion of neurons and glia in the brain remained stable. From the current pilot study, we found that despite tissue-specific epigenetic changes and cellular heterogeneity, blood can serve as a surrogate for GC-induced changes in the brain.
AB - Chronic exposure to glucocorticoids (GCs) can lead to psychiatric complications through epigenetic mechanisms such as DNA methylation (DNAm). We sought to determine whether epigenetic changes in a peripheral tissue can serve as a surrogate for those in a relatively inaccessible tissue such as the brain. DNA extracted from the hippocampus and blood of mice treated with GCs or vehicle solution was assayed using a genome-wide DNAm platform (Methyl-Seq) to identify differentially methylated regions (DMRs) induced by GC treatment. We observed that ∼70% of the DMRs in both tissues lost methylation following GC treatment. Of the 3,095 DMRs that mapped to the same genes in both tissues, 1,853 DMRs underwent DNAm changes in the same direction. Interestingly, only 209 DMRs (<7%) overlapped in genomic coordinates between the 2 tissues, suggesting tissue-specific differences in GC-targeted loci. Pathway analysis showed that the DMR-associated genes were members of pathways involved in metabolism, immune function, and neurodevelopment. Also, changes in cell type composition of blood and brain were examined by fluorescence-activated cell sorting. Separation of the cortex into neuronal and non-neuronal fractions and the leukocytes into T-cells, B-cells, and neutrophils showed that GC-induced methylation changes primarily occurred in neurons and T-cells, with the blood tissue also undergoing a shift in the proportion of constituent cell types while the proportion of neurons and glia in the brain remained stable. From the current pilot study, we found that despite tissue-specific epigenetic changes and cellular heterogeneity, blood can serve as a surrogate for GC-induced changes in the brain.
KW - Biomarker
KW - Cushing's disease
KW - DNA methylation
KW - blood-brain correlation
KW - epigenetics
KW - glucocorticoids
KW - tissue heterogeneity
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U2 - 10.1080/15592294.2017.1334025
DO - 10.1080/15592294.2017.1334025
M3 - Article
C2 - 28557603
AN - SCOPUS:85026349742
SN - 1559-2294
VL - 12
SP - 637
EP - 652
JO - Epigenetics
JF - Epigenetics
IS - 8
ER -