Hypoxia induces alterations in tRNA modifications involved in translational control.
Hypoxia induces alterations in tRNA modifications involved in translational control.
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DOI：
10.1186/s12915-023-01537-x
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发表时间：
2023-02-21
期刊：
影响因子：
5.4
通讯作者：
Zhang, Yunfang
中科院分区：
文献类型：
--
作者：
Guo, Huanping;Xia, Lin;Wang, Wei;Xu, Wei;Shen, Xipeng;Wu, Xiao;He, Tong;Jiang, Xuelin;Xu, Yinying;Zhao, Pan;Tan, Dongmei;Zhang, Xi;Zhang, Yunfang
适应高海拔低压缺氧已被证明需要一套生理特性，通过相关的一套遗传修饰，以及转录组调控。这导致了个体对高海拔缺氧的终生适应和种群的世代进化，例如在西藏。此外，对环境暴露敏感的RNA修饰已被证明在维持器官的生理功能方面发挥关键的生物学作用。然而，在低压低氧暴露下小鼠组织中的动态RNA修饰景观和相关的分子机制仍有待充分理解。在这里，我们探讨了小鼠组织中多种RNA修饰的组织特异性分布模式。通过应用LC-MS/MS依赖的RNA修饰检测平台，我们确定了小鼠组织中总RNA、tRNA富集片段和17-50-nt sncRNA中多种RNA修饰的分布;这些模式与不同组织中RNA修饰修饰剂的表达水平相关。此外，在模拟高海拔（超过5500米）低压缺氧小鼠模型中，不同RNA组的RNA修饰的组织特异性丰度敏感地改变，小鼠外周血和多个组织中的缺氧反应被激活。RNA酶消化实验表明，缺氧暴露下RNA修饰丰度的改变影响组织总tRNA富集片段和分离的单个tRNA，如tRNAAla，tRNAval，tRNAGlu和tRNALeu的分子稳定性。体外转染实验表明，睾丸总tRNA富集片段从缺氧组转染到GC-2spd细胞衰减细胞增殖率，并导致在细胞中的整体新生蛋白质合成减少。我们的研究结果表明，丰富的RNA修饰不同类别的RNA在生理条件下是组织特异性的，并响应于低压缺氧暴露在组织特异性的方式。从机制上讲，在低压缺氧下tRNA修饰的失调减弱了细胞增殖速率，促进了tRNA对RNA酶的敏感性，并导致整体新生蛋白质合成的减少，表明tRNA表位转录组改变在对环境缺氧暴露的适应性反应中起着积极作用。在线版本包含补充材料，可通过10.1186/s12915-023-01537-x获得。
Adaptation to high-altitude hypobaric hypoxia has been shown to require a set of physiological traits enabled by an associated set of genetic modifications, as well as transcriptome regulation. These lead to both lifetime adaptation of individuals to hypoxia at high altitudes and generational evolution of populations as seen for instance in those of Tibet. Additionally, RNA modifications, which are sensitive to environmental exposure, have been shown to play pivotal biological roles in maintaining the physiological functions of organs. However, the dynamic RNA modification landscape and related molecular mechanisms in mouse tissues under hypobaric hypoxia exposure remain to be fully understood. Here, we explore the tissue-specific distribution pattern of multiple RNA modifications across mouse tissues. By applying an LC-MS/MS-dependent RNA modification detection platform, we identified the distribution of multiple RNA modifications in total RNA, tRNA-enriched fragments, and 17–50-nt sncRNAs across mouse tissues; these patterns were associated with the expression levels of RNA modification modifiers in different tissues. Moreover, the tissue-specific abundance of RNA modifications was sensitively altered across different RNA groups in a simulated high-altitude (over 5500 m) hypobaric hypoxia mouse model with the activation of the hypoxia response in mouse peripheral blood and multiple tissues. RNase digestion experiments revealed that the alteration of RNA modification abundance under hypoxia exposure impacted the molecular stability of tissue total tRNA-enriched fragments and isolated individual tRNAs, such as tRNAAla, tRNAval, tRNAGlu, and tRNALeu. In vitro transfection experiments showed that the transfection of testis total tRNA-enriched fragments from the hypoxia group into GC-2spd cells attenuated the cell proliferation rate and led to a reduction in overall nascent protein synthesis in cells. Our results reveal that the abundance of RNA modifications for different classes of RNAs under physiological conditions is tissue-specific and responds to hypobaric hypoxia exposure in a tissue-specific manner. Mechanistically, the dysregulation of tRNA modifications under hypobaric hypoxia attenuated the cell proliferation rate, facilitated the sensitivity of tRNA to RNases, and led to a reduction in overall nascent protein synthesis, suggesting an active role of tRNA epitranscriptome alteration in the adaptive response to environmental hypoxia exposure. The online version contains supplementary material available at 10.1186/s12915-023-01537-x.
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