Genome-Wide DNA Methylation Profiling Reveals Epigenetic Changes in the Rat Nucleus Accumbens Associated With Cross-Generational Effects of Adolescent THC Exposure.
Genome-Wide DNA Methylation Profiling Reveals Epigenetic Changes in the Rat Nucleus Accumbens Associated With Cross-Generational Effects of Adolescent THC Exposure.
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DOI：
10.1038/npp.2015.155
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发表时间：
2015-12
期刊：
影响因子：
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通讯作者：
Hurd YL
中科院分区：
文献类型：
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作者：
Watson CT;Szutorisz H;Garg P;Martin Q;Landry JA;Sharp AJ;Hurd YL
众所周知，在发育的关键时期接触药物会产生持久的影响，增加一个人患精神健康障碍的风险。新出现的证据也表明，接触毒品甚至有可能影响后代。我们之前的工作表明，在Long-Evans大鼠模型中，青少年暴露于Δ9-四氢大麻酚(大麻的主要精神活性成分)会影响未暴露于该药物的后续(F1)代的奖赏相关行为和基因调控。然而，关于潜在的表观遗传后果的问题仍然存在。在目前的研究中，使用相同的大鼠模型，我们使用增强的简化表示亚硫酸盐测序来询问伏隔核的表观基因组，这是大脑中参与奖励处理的关键区域。这项分析比较了16只有亲代THC暴露的动物和16只没有亲代接触的动物，以表征DNA甲基化的相关系统水平的变化。我们在F1成人中确定了1027个与父母THC暴露相关的差异甲基化区域(DMR)，每个区域都由多个CPG代表。这些DMR主要落在内含子、外显子和基因间隔内，同时显示出基因启动子的显著缺失。由此，我们发现了一个参与谷氨酸能突触调节的DMR相关基因网络，这些基因在伏隔核中的表达也发生了变化。这些数据为药物相关的跨世代表观遗传效应提供了新的见解，并为研究人员探索药物滥用脆弱性的新神经生物学系统提供了有用的资源。
Drug exposure during critical periods of development is known to have lasting effects, increasing one's risk for developing mental health disorders. Emerging evidence has also indicated the possibility for drug exposure to even impact subsequent generations. Our previous work demonstrated that adolescent exposure to Δ9-tetrahydrocannabinol (THC), the main psychoactive component of marijuana (Cannabis sativa), in a Long-Evans rat model affects reward-related behavior and gene regulation in the subsequent (F1) generation unexposed to the drug. Questions, however, remained regarding potential epigenetic consequences. In the current study, using the same rat model, we employed Enhanced Reduced Representation Bisulfite Sequencing to interrogate the epigenome of the nucleus accumbens, a key brain area involved in reward processing. This analysis compared 16 animals with parental THC exposure and 16 without to characterize relevant systems-level changes in DNA methylation. We identified 1027 differentially methylated regions (DMRs) associated with parental THC exposure in F1 adults, each represented by multiple CpGs. These DMRs fell predominantly within introns, exons, and intergenic intervals, while showing a significant depletion in gene promoters. From these, we identified a network of DMR-associated genes involved in glutamatergic synaptic regulation, which also exhibited altered mRNA expression in the nucleus accumbens. These data provide novel insight into drug-related cross-generational epigenetic effects, and serve as a useful resource for investigators to explore novel neurobiological systems underlying drug abuse vulnerability.