Southey Bruce R, Sunderland Gloria R, Gomez Andrea N, Bhamidi Sreelaya, Rodriguez-Zas Sandra L
Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801 USA.
Informatics Program, University of Illinois at Urbana-Champaign, Urbana, IL 61820 USA.
Gene. 2025 Mar 20;942:149215. doi: 10.1016/j.gene.2025.149215. Epub 2025 Jan 3.
The alternative splicing of a gene results in distinct transcript isoforms that can result in proteins that differ in function. Alternative splicing processes are prevalent in the brain, have varying incidence across brain regions, and can present sexual dimorphism. Exposure to opiates and other substances of abuse can also alter the type and incidence of the splicing process and the relative abundance of the isoforms produced. The disruption of alternative splicing patterns associated with sex differences and morphine exposure in the prefrontal cortex of a pig model was studied. The numbers of genes presenting one or more significant (FDR-adjusted p-value < 0.05) alternative splicing events were 933 and 1,368 genes when comparing females relative to males and morphine- relative to saline-treated animals, respectively. The sex-dependent opioid effect was most extreme in the contrast between morphine- versus saline-treated males with 1,934 significantly differentially spliced genes. The most frequent and significant alternative splicing type was skipped exon (∼56 % event), followed by retained intron (∼15 % events). The pathways encompassing a significant number of differentially spliced genes included axon guidance, glutamatergic synapses, circadian rhythm, and lysine degradation. Genes in these pathways included ROBO1, SEMA6C, GRIN3A, GRM2, ARNTL, CLOCK, HYKK, and DOT1L. Transcription factors ETV7 and DMAP1 presented a significant number of differentially spliced target genes. The distribution of the genes presenting differential alternative splicing in the axon guidance and circadian rhythm pathways indicates that this regulatory mechanism impacts hubs and peripheral genes. The identification of sexual dimorphism in the effect of morphine across multiple pathways confirms the necessity to explore the effects of drugs of abuse within sex. Altogether, our findings advance the understanding of the response to factors that can impact the activity of excitatory synapses by modulating transcriptional mechanisms that support the plasticity of the prefrontal cortex.
基因的可变剪接会产生不同的转录异构体，这些异构体可能导致功能不同的蛋白质。可变剪接过程在大脑中普遍存在，在不同脑区的发生率各异，并且可能存在性别差异。接触阿片类药物和其他滥用物质也会改变剪接过程的类型和发生率以及所产生异构体的相对丰度。我们研究了猪模型前额叶皮质中与性别差异和吗啡暴露相关的可变剪接模式的破坏情况。在比较雌性与雄性以及吗啡处理组与生理盐水处理组动物时，出现一个或多个显著（FDR校正P值<0.05）可变剪接事件的基因数量分别为933个和1368个基因。吗啡对性别的依赖性作用在吗啡处理的雄性与生理盐水处理的雄性对比中最为显著，有1934个显著差异剪接基因。最常见且显著的可变剪接类型是外显子跳跃（约56%的事件），其次是内含子保留（约15%的事件）。包含大量差异剪接基因的通路包括轴突导向、谷氨酸能突触、昼夜节律和赖氨酸降解。这些通路中的基因包括ROBO1、SEMA6C、GRIN3A、GRM2、ARNTL、CLOCK、HYKK和DOT1L。转录因子ETV7和DMAP1有大量差异剪接的靶基因。在轴突导向和昼夜节律通路中呈现差异可变剪接的基因分布表明，这种调控机制影响枢纽基因和外周基因。吗啡在多个通路中的作用存在性别差异的鉴定结果证实了有必要在不同性别中探索滥用药物的影响。总之，我们的研究结果推进了对通过调节支持前额叶皮质可塑性的转录机制来影响兴奋性突触活动的因素的反应的理解。
