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Genome-wide analysis of the nucleus accumbens identifies DNA methylation signals differentiating low/binge from heavy alcohol drinking

机译：全基因组分析伏隔核识别DNA甲基化信号区分低度/暴饮暴食与重度饮酒

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Alcohol use disorders encompass a range of drinking levels and behaviors, including low, binge and heavy drinking. In this regard, investigating the neural state of individuals who chronically self-administer lower doses of alcohol may provide insight into mechanisms that prevent the escalation of alcohol use. DNA methylation is one of the epigenetic mechanisms that stabilizes adaptations in gene expression and has been associated with alcohol use. Thus, we investigated DNA methylation, gene expression and the predicted neural effects in the nucleus accumbens of male rhesus macaques categorized as “low” or “binge” drinkers, compared to “alcohol-naïve” and “heavy” drinkers based on drinking patterns during a 12 month alcohol self-administration protocol. Using genome-wide CpG-rich region enrichment and bisulfite sequencing, the methylation levels of 2.6 million CpGs were compared between alcohol naïve (AN), low/binge (L/BD) and heavy/very heavy (H/VHD) drinking subjects (n=24). Through regional clustering analysis, we identified nine significant differential methylation regions (DMRs) that specifically distinguished ANs and L/BDs, and then compared those DMRs among H/VHDs. The DMRs mapped to genes encoding ion channels, receptors, cell adhesion molecules and cAMP, NF-κβ and Wnt signaling pathway proteins. Two of the DMRs, linked to PDE10A and PKD2L2, were also differentially methylated in H/VHDs, suggesting an alcohol-dose independent effect. However two other DMRs, linked to the CCBE1 and FZD5 genes, had L/BD methylation levels that significantly differed from both ANs and H/VHDs. The remaining 5 DMRs also differentiated L/BDs and ANs, however H/VHDs methylation levels were not distinguishable from either of the two groups. Functional validation of two DMRs, linked to FZD5 and PDE10A, support their role in regulating gene expression and exon usage, respectively. In summary, the findings demonstrate that L/BD is associated with unique DNA methylation signatures in the primate NAcc, and identifies synaptic genes that may play a role in preventing the escalation of alcohol use.
机译：饮酒障碍包括各种饮酒水平和行为，包括低度饮酒，暴饮暴食和大量饮酒。在这方面，调查长期自我服用低剂量酒精的人的神经状态可能有助于深入了解防止酒精使用量增加的机制。 DNA甲基化是表观遗传机制之一，可稳定基因表达的适应性，并与酒精的使用有关。因此，我们根据在饮酒过程中的饮酒方式，比较了“无酒精”和“重度”饮酒者的男性恒河猴猕猴的伏隔核中的甲基化，基因表达和预测的神经效应。十二个月的酒精自我管理方案。使用全基因组范围内富含CpG的区域富集和亚硫酸氢盐测序，比较了未饮酒（AN），低/暴饮暴食（L / BD）和重/非常重（H / VHD）饮酒受试者的260万CpG的甲基化水平（ n = 24）。通过区域聚类分析，我们确定了9个显着的差异甲基化区域（DMR），这些区域专门区分了AN和L / BD，然后在H / VHD之间比较了这些DMR。 DMR定位于编码离子通道，受体，细胞粘附分子以及cAMP，NF-κβ和Wnt信号通路蛋白的基因。与PDE10A和PKD2L2相连的两个DMR在H / VHDs中也被甲基化，表明不依赖酒精剂量。然而，与CCBE1和FZD5基因相关的另外两个DMR具有与AN和H / VHD明显不同的L / BD甲基化水平。其余5个DMR也区分了L / BD和AN，但是H / VHDs的甲基化水平与两组均没有区别。与FZD5和PDE10A链接的两个DMR的功能验证分别支持它们在调节基因表达和外显子使用中的作用。总而言之，这些发现表明L / BD与灵长类动物NAcc中独特的DNA甲基化特征相关，并鉴定出可能在防止酒精使用量增加中起作用的突触基因。

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