Mature Neurons’ sensitivity to oxidative stress is epigenetically programmed by alternative splicing and mRNA stability
Mature Neurons’ sensitivity to oxidative stress is epigenetically programmed by alternative splicing and mRNA stability
复制标题
成熟神经元对氧化应激的敏感性是通过选择性剪接和 mRNA 稳定性进行表观遗传编程的
DOI：
10.1101/2021.12.25.472549
复制
发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Kuniyasu Niizuma
中科院分区：
文献类型：
--
作者：
Yuan Zhou;Sherif Rashad;Teiji Tominaga;Kuniyasu Niizuma
神经元分化是一个复杂的过程，涉及广泛的形态、转录、代谢和功能变化，这些变化决定了神经元谱系的承诺。对表观遗传和表观转录重编程在神经元分化和成熟过程中所起的作用了解甚少。为了描绘神经元分化和成熟过程中转录组学和表观遗传学变化的全貌，我们分化了SH-SY5Y细胞，并对分化和未分化的细胞进行了RNA测序。共观察到728个差异表达基因（deg）富集于突触信号通路和细胞形态发生通路。此外，转录组全mRNA稳定性分析显示，稳定性改变的基因在氧化还原稳态途径中异常富集。成熟神经元对氧化应激高度敏感，这在神经退行性疾病的病理生理中至关重要。我们的研究结果表明，这种高度敏感性是在mRNA稳定性水平（即表观遗传）而不是在转录水平上调节的。选择性剪接分析显示外显子跳变和形态发生相关途径富集的选择性mRNA亚型。另外，可选的5和3 '端剪接位点、内含子保留和互斥外显子事件都集中在翻译和翻译起始途径中，这表明可选剪接对神经元成熟后翻译的潜在影响。剪接基序分析显示，rbp的丰富基序可以调节各种剪接类型，并进一步与神经元分化和成熟过程中不同的表型变化相关。在这里，我们提出了广泛的探索转录和表观遗传变化及其与神经元分化过程的潜在关联，为理解神经元功能和行为的分子机制提供了新的见解。
Neuronal differentiation is a complex process that entails extensive morphological, transcriptional, metabolic, and functional changes that dictate neuronal lineage commitment. Much less understood is the role that epigenetic and epi-transcriptional reprogramming plays in the process of neuronal differentiation and maturation. To depict the whole landscape of transcriptomics and epigenetic changes during neuronal differentiation and maturation, we differentiated SH-SY5Y cells and performed RNA sequencing on differentiated and undifferentiated cells. 728 differentially expressed genes (DEGs) enriched in synaptic signaling and cell morphogenesis pathways were observed. Moreover, transcriptome-wide mRNA stability profiling revealed that genes with altered stability were exceptionally enriched for redox homeostasis pathways. Mature neurons are known to be highly sensitive to oxidative stress, which is crucial in the pathophysiology of neurodegenerative disease. Our results suggest that this heightened sensitivity is regulated at the mRNA stability level (i.e., epigenetic) rather than at the transcriptional level. Alternative splicing analysis revealed the exon skipping and alternative mRNA isoforms enriched for morphogenesis related pathway. Alternatively, alternative 5 and 3 prime splicing site, intron retention and mutually exclusive exon events exclusively clustered in the translation and translation initiation pathways, suggesting the potential effect of alternative splicing on translation following neuronal maturation. Splice motif analysis revealed enriched motifs for RBPs that regulate various splice types and can be further correlated to distinct phenotypical changes during neuronal differentiation and maturation. Here we present an extensive exploration of the transcriptional and epigenetic changes and their potential association with the process of neuronal differentiation, providing a new insight into understanding the molecular mechanism of neuronal function and behavior.
登录
查看更多内容
影响因子：
5
作者：
Su CH;D D;Tarn WY
通讯作者：
Tarn WY
影响因子：
5.5
作者：
Zhenxun Wang;D. Chatterjee;H. Y. Jeon;Martin Akerman;M. V. Vander Heiden;L. Cantley;A. Krainer
通讯作者：
Zhenxun Wang;D. Chatterjee;H. Y. Jeon;Martin Akerman;M. V. Vander Heiden;L. Cantley;A. Krainer
DOI：
10.1016/c2011-0-07685-8
发表时间：
2013
期刊：
--
影响因子：
--
作者：
J. Rubenstein;P. Rakic
通讯作者：
J. Rubenstein;P. Rakic
影响因子：
--
作者：
Murillo JR;Goto-Silva L;Sánchez A;Nogueira FCS;Domont GB;Junqueira M
通讯作者：
Junqueira M
影响因子：
3.3
作者：
Hui-Ming Zhu;Robert A. Hasman;Victoria A Barron;G. Luo;H. Lou
通讯作者：
Hui-Ming Zhu;Robert A. Hasman;Victoria A Barron;G. Luo;H. Lou