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. 2018 Sep 10;11:322.
doi: 10.3389/fnmol.2018.00322. eCollection 2018.

A DNA Methylation Signature of Addiction in T Cells and Its Reversal With DHEA Intervention

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Free PMC article

A DNA Methylation Signature of Addiction in T Cells and Its Reversal With DHEA Intervention

Elad Lax et al. Front Mol Neurosci. .
Free PMC article

Abstract

Previous studies in animal models of cocaine craving have delineated broad changes in DNA methylation profiles in the nucleus accumbens. A crucial factor for progress in behavioral and mental health epigenetics is the discovery of epigenetic markers in peripheral tissues. Several studies in primates and humans have associated differences in behavioral phenotypes with changes in DNA methylation in T cells and brain. Herein, we present a pilot study (n = 27) showing that the T cell DNA methylation profile differentiates persons with a substance use disorder from controls. Intervention with dehydroepiandrosterone (DHEA), previously shown to have a long-term therapeutic effect on human addicts herein resulted in reversal of DNA methylation changes in genes related to pathways associated with the addictive state.

Keywords: DNA methylation; dehydroepiandrosterone (DHEA); drug abuse; drug-addiction; genome-wide analysis.

Figures

FIGURE 1
FIGURE 1
DNA methylation differences associated with addiction. (A) Box plot of average methylation of sites that are differentially methylated between addicted and healthy controls. Bottom panel: the average methylation of genes that become less methylated (hypomethylation) and more methylated (hypermethylation) in addicts ∗∗∗p < 2.2E-16; Mann–Whitney test. (B) Heat map showing clustering by one minus Pearson correlations of healthy controls and addicts using the 5,532 differentially methylated genes (4,458 probes were hypomethylated and 1,074 hypermethylated in addicts).
FIGURE 2
FIGURE 2
Functional footprint of differentially methylated gene promoters in addicts. (A) Canonical gene-pathways that are enriched with genes that are hypermethylated in addicts. (B) Canonical gene-pathways that are enriched with genes that are hypomethylated in addicted persons. Arrows indicate neurobiological-related pathways further analyzed for the effect of DHEA.
FIGURE 3
FIGURE 3
The effect of DHEA intervention on neurobiological-related gene promoters. (A) Gene promoters hypermethylated in addicts and related to the “Reelin Signaling in Neurons” pathway. (B) Gene promoters hypermethylated in addicts and related to the “Corticotrophin Releasing Hormone Signaling” pathway. (C) Gene promoters hypomethylated in addicts and related to the “Catecholamines, Serotonin, and Ethanol Degradation” pathway. Methylation values were determined using Illumina 450K arrays. Statistical significance was determined using one-way ANOVA analyses followed by Bonferroni correction for multiple testing and Tukey post hoc test. p < 0.05, ∗∗p < 0.01, n.s.- ANOVA did not stand Bonferroni correction (p > 0.05 for the main effect).
FIGURE 4
FIGURE 4
DNA methylation levels of CG sites that correlate with the PANAS negative affect score. Probes significantly correlated with PANAS negative affect score of addicts are depicted (p < 0.05; FDR < 0.2).
FIGURE 5
FIGURE 5
Overlap between genes that are differentially methylated in T-cells from addicts and differentially methylated genes in cocaine-intake trained-rats nucleus accumbens. (A) Lists of differentially methylated genes in addicts T-cells and cocaine self-administration trained-rats nucleus accumbens were compared. A significant overlap was found for hypo-methylated (left) but not hyper-methylated (right) genes using Fisher hypergeometric test. (B) Table of pathways significantly over-represented in the list of genes commonly hypo-methylated in human T-cells and rat nucleus accumbens.
FIGURE 6
FIGURE 6
Overlap between differentially methylated CpG in alcohol users and current findings. (A) A significant overlap was observed between our list of differentially methylated CpGs and a list of alcohol use markers found by Liu et al. (2018). (B) A significant overlap was observed between our list of differentially methylated CpGs and a list of alcohol use markers found by Philibert et al. (2018). Significance was assessed by the Fisher hyper-geometric test.

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