Methamphetamine induced regional-specific transcriptomic and epigenetic changes in rat brain [ATAC-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.本研究探究了大鼠脑四个区域（伏隔核、齿状回、阿蒙角及室管膜下区）在甲基苯丙胺（METH）过量暴露后的转录组学与表观遗传学应答反应。本研究发现，甲基苯丙胺过量给药24小时后，大鼠四个脑区中15.6%的基因出现表达改变，27.6%的开放染色质区域的染色质可及性发生异常。值得注意的是，其中仅少数差异表达基因（differentially expressed genes, DEGs）与差异开放染色质区域（differentially accessible regions, DARs）同时受到调控影响。在所分析的四个大鼠脑区中，共有149个转录因子（transcription factors, TFs）及31个表观遗传因子因甲基苯丙胺过量给药而发生显著表达变化。甲基苯丙胺过量暴露还致使齿状回与阿蒙角内的基因表达及染色质可及性调控模式出现逆转。约70%的甲基苯丙胺诱导的染色质可及性改变区域显著富集于神经生物学过程，且与人类基因组存在保守共享序列。其中大量保守序列为脑特异性活跃增强子，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，大鼠不同脑区对甲基苯丙胺过量暴露存在强烈的区域特异性转录组学与表观遗传学应答反应，并阐明了与甲基苯丙胺过量相关的区域特异性基因调控网络的保守性。总体而言，本研究为深入解析人类大脑对甲基苯丙胺过量的分子应答机制提供了关键线索。