Methamphetamine induced regional-specific transcriptomic and epigenetic changes in rat brain [RNA-seq]

We investigated the transcriptomic and epigenetic responses to a METH overdose in four regions of rat brain, including the nucleus accumbens, dentate gyrus, Ammon’s horn, and subventricular zone. We found that 24 hours after the METH overdose, 15.6% of genes changed expression and 27.6% of open-chromatin regions altered chromatin accessibility in all four rat brain regions. Interestingly, only a few of those differentially expressed genes (DEGs) and differentially accessible regions (DARs) were simultaneously affected. Among the four rat brain regions analyzed, 149 transcription factors (TFs) and 31 epigenetic factors were significantly affected by the METH overdose. The METH overdose also resulted in reversed regulation patterns of both gene and chromatin accessibility in the dentate gyrus and Ammon’s horn. About 70% of METH-induced chromatin accessibility alterations are highly enriched in neurological processes and shared conserved sequences to the human genome. Many of these conserved regions were active brain-specific enhancers and harbored the SNPs associated with human neurological functions and diseases. Our results indicate strong region-specific transcriptomic and epigenetic responses to a METH overdose in distinct rat brain regions. We describe the conservation of region-specific gene regulatory networks associated with a METH overdose. Overall, our study provides clues to a better understanding of the molecular responses to METH overdose in the human brain.本研究针对大鼠脑内四个脑区——伏隔核（nucleus accumbens）、齿状回（dentate gyrus）、海马Ammon角（Ammon’s horn）以及室管膜下区（subventricular zone），探究了甲基苯丙胺（METH）过量暴露引发的转录组学与表观遗传学应答。研究发现，在METH过量暴露24小时后，四个脑区中共计15.6%的基因出现表达量改变，27.6%的开放染色质区域发生染色质可及性变化。有趣的是，仅少数差异表达基因（differentially expressed genes, DEGs）与差异可及区域（differentially accessible regions, DARs）同时受到该处理的影响。在所分析的四个大鼠脑区中，共有149个转录因子（transcription factors, TFs）与31个表观遗传因子因METH过量暴露发生显著调控变化。METH过量暴露还使齿状回与海马Ammon角内的基因表达及染色质可及性出现调控模式反转现象。约70%的METH诱导型染色质可及性改变显著富集于神经生物学过程，且与人类基因组共享保守序列。这些保守区域中有大量为活跃的脑特异性增强子，且携带有与人类神经功能及疾病相关的单核苷酸多态性（single nucleotide polymorphisms, SNPs）。本研究结果表明，不同大鼠脑区对METH过量暴露呈现出显著的脑区特异性转录组学与表观遗传学应答。本研究阐明了与METH过量暴露相关的脑区特异性基因调控网络的保守性特征。综上，本研究为深入解析人类大脑对METH过量暴露的分子应答机制提供了重要线索。