PDF(Pubmed)
Abstract：
Both aggressive and aggression-deprived (AD) individuals represent pathological cases extensively studied in psychiatry and substance abuse disciplines. We employed the animal model of chronic social conflicts curated in our laboratory for over 30 years. In the study, we pursued the task of evaluation of the key events in the dorsal striatum transcriptomes of aggression-experienced mice and AD species, as compared with the controls, using RNA-seq profiling. We evaluated the alternative splicing-mediated transcriptome dynamics based on the RNA-seq data. We confined our attention to the exon skipping (ES) events as the major AS type for animals. We report the concurrent posttranscriptional and posttranslational regulation of the ES events observed in the phosphorylation cycles (in phosphoproteins and their targets) in the neuron-specific genes of the striatum. Strikingly, we found that major neurospecific splicing factors (Nova1, Ptbp1, 2, Mbnl1, 2, and Sam68) related to the alternative splicing regulation of cAMP genes (Darpp-32, Grin1, Ptpn5, Ppp3ca, Pde10a, Prkaca, Psd95, and Adora1) are upregulated specifically in aggressive individuals as compared with the controls and specifically AD animals, assuming intense switching between isoforms in the cAMP-mediated (de)phosphorylation signaling cascade. We found that the coding alternative splicing events were mostly attributed to synaptic plasticity and neural development-related proteins, while the nonsense-mediated decay-associated splicing events are mostly attributed to the mRNA processing of genes, including the spliceosome and splicing factors. In addition, considering the gene families, the transporter (Slc) gene family manifested most of the ES events. We found out that the major molecular systems employing AS for their plasticity are the \'spliceosome\', \'chromatin rearrangement complex\', \'synapse\', and \'neural development/axonogenesis\' GO categories. Finally, we state that approximately 35% of the exon skipping variants in gene coding regions manifest the noncoding variants subject to nonsense-mediated decay, employed as a homeostasis-mediated expression regulation layer and often associated with the corresponding gene expression alteration.
摘要：
侵略性和侵略性剥夺（AD）个体都代表了精神病学和药物滥用学科中广泛研究的病理病例。我们采用了在实验室中策划的30多年的慢性社会冲突动物模型。在研究中,我们追求的任务是评估有侵略经历的小鼠和AD物种的背侧纹状体转录组中的关键事件，与对照组相比，使用RNA-seq分析。我们基于RNA-seq数据评估了可变剪接介导的转录组动力学。我们将注意力集中在外显子跳跃（ES）事件上，这是动物的主要AS类型。我们报告了在纹状体神经元特异性基因的磷酸化周期（在磷蛋白及其靶标中）中观察到的ES事件的同时转录后和翻译后调控。引人注目的是，我们发现主要的神经特异性剪接因子（Nova1，Ptbp1，2，Mbnl1，2和Sam68）与cAMP基因（Darpp-32，Grin1，Ptpn5，Ppp3ca，Pde10a,普卡卡,与对照，特别是AD动物相比，Psd95和Adora1）在攻击性个体中特别上调，假设cAMP介导的（去）磷酸化信号级联中同种型之间的强烈转换。我们发现编码可变剪接事件主要归因于突触可塑性和神经发育相关蛋白。虽然无义介导的衰变相关剪接事件主要归因于基因的mRNA加工，包括剪接体和剪接因子。此外,考虑到基因家族，转运体（Slc）基因家族表现出大多数ES事件。我们发现，使用AS的主要分子系统的可塑性是\'剪接体\'，\'染色质重排复合物\',\'突触\',和“神经发育/轴突发生”GO类。最后,我们指出，基因编码区中大约35%的外显子跳跃变体表现出受无义介导的衰变的非编码变体，用作稳态介导的表达调节层，通常与相应的基因表达改变有关。
