Li Chen, Gong Fu-Xing, Yang Zhigang, Fu Xin, Shi Hang, Sun Xuejian, Zhang Xiaorong, Xiao Ran
Research Center of Plastic Surgery Hospital, CAMS Key Laboratory of Tissue and Organ Regeneration, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, CAMS Key Laboratory for Prevention and Control of Hematological Disease Treatment Related Infection, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
J Biol Chem. 2025 Apr 25;301(6):108542. doi: 10.1016/j.jbc.2025.108542.
Alternative splicing (AS) diversifies protein expression and contributes to species-specific differences in organ development. Here, we focused on stage-specific splicing variants and their correlation with disease in humans compared to mice during brain and heart development. Temporal transcriptomic analysis revealed that splicing factors (SFs) can accurately classify organ developmental stages, and 5 SFs were identified specifically upregulated in humans during organogenesis. Additionally, inter-stage splicing variations were identified across analogous human and mouse developmental stages. Developmentally dynamic alternative splicing genes (devASGs) were enriched in various neurodevelopmental disorders in both species, with the most significant changes observed in human newborn brain and 16 weeks post-conception heart. Intriguingly, diseases specifically enriched in humans were primarily associated with neuro-muscular dysfunction, and human-specific neuromuscular devASGs were linked to mannose glycosylation and ciliary motility. These findings highlight the significance of SFs and AS events in organogenesis and inform the selection of appropriate models for translational research.
可变剪接（AS）使蛋白质表达多样化，并导致器官发育中的物种特异性差异。在这里，我们重点研究了人类与小鼠在脑和心脏发育过程中特定阶段的剪接变体及其与疾病的相关性。时间转录组分析表明，剪接因子（SFs）可以准确地对器官发育阶段进行分类，并且在器官发生过程中，有5种SFs在人类中被特异性上调。此外，在类似的人类和小鼠发育阶段中发现了阶段间剪接变异。发育动态可变剪接基因（devASGs）在两个物种的各种神经发育障碍中均有富集，在人类新生儿脑和受孕后16周的心脏中观察到的变化最为显著。有趣的是，人类中特异性富集的疾病主要与神经肌肉功能障碍有关，而人类特异性神经肌肉devASGs与甘露糖糖基化和纤毛运动有关。这些发现突出了SFs和AS事件在器官发生中的重要性，并为转化研究中合适模型的选择提供了依据。
