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首页> 外文期刊>Alcohol >Genome-wide analysis of the nucleus accumbens identifies DNA methylation signals differentiating low/binge from heavy alcohol drinking
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Genome-wide analysis of the nucleus accumbens identifies DNA methylation signals differentiating low/binge from heavy alcohol drinking

机译：基因组 - 核常量分析鉴定DNA甲基化信号与重度醇饮用的低/静脉分化

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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 core (NAcc) of male rhesus macaques categorized as "low" or "binge" drinkers, compared to "alcohol-naive" 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-naive (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-kappa beta 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 five 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 that the methylation signatures identify synaptic genes that may play a role in preventing the escalation of alcohol use. Published by Elsevier Inc.
机译：酒精使用障碍包括一系列饮用水平和行为，包括低，狂，饮酒。在这方面，调查长期自我管理较低剂量的酒精的个体的神经状态可以提供有助于防止饮酒升级的机制。 DNA甲基化是稳定基因表达的适应性的表观遗传机制之一，并与酒精使用有关。因此，我们研究了DNA甲基化，基因表达，以及雄性羊颈核心（NACC）的预测神经效应，被分类为“低”或“狂欢”饮酒者，与“酒类天真”和“重”饮酒者相比基于12个月的酒精自我管理协议期间的饮酒模式。利用基因组CPG的地区富集和亚硫酸氢盐测序，比较醇 - 幼稚（AN），低/虱（L / BD）和重/非常重（H / VHD）饮用之间的甲基化水平。受试者（n = 24）。通过区域聚类分析，我们鉴定了九个明显的差分甲基化区域（DMRS），其特异性区分ANS和L / BD，然后比较了H / VHD中的那些DMRS。将DMR映射到编码离子通道，受体，细胞粘附分子和阵营，NF-Kappaβ和WNT信号传导蛋白的基因。与PDE10A和PKD2L2相关的两种DMRS也在H / VHD中差异甲基化，表明醇剂量无关。然而，与CCBE1和FZD5基因相关的另外两种DMRS具有L / BD甲基化水平，其与AN和H / VHD有显着不同。剩下的五个DMR也有区别的L / BDS和ANS。然而，H / VHDS甲基化水平与两组中的任何一个都不可区分。与FZD5和PDE10A相关的两个DMR的功能验证，分别支持其在调节基因表达和外显子使用中的作用。总之，研究结果表明，L / BD在灵长类动物NACC中与独特的DNA甲基化签名相关，并且甲基化签名鉴定可能在防止醇类升级中发挥作用的突触基因。 elsevier公司发布

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