Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, 400037, China.
Chongqing Medical University, Chongqing, 400016, China.
BMC Biol. 2023 Feb 21;21(1):39. doi: 10.1186/s12915-023-01537-x.
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 tRNA, tRNA, tRNA, and tRNA. 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.
适应高海拔低氧环境需要一系列生理特征，这些特征是由相关的遗传修饰以及转录组调节产生的。这些特征不仅导致个体在高海拔地区的终身适应低氧环境，而且还导致了种群的世代进化，例如西藏的那些种群。此外，RNA 修饰对环境暴露敏感，已经被证明在维持器官的生理功能方面发挥着关键的生物学作用。然而，在低氧环境暴露下，小鼠组织中动态的 RNA 修饰景观和相关的分子机制仍有待充分理解。在这里，我们探索了多种 RNA 修饰在小鼠组织中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，我们在小鼠组织的总 RNA、tRNA 富集片段和 17-50nt sncRNA 中鉴定了多种 RNA 修饰的分布；这些模式与不同组织中 RNA 修饰修饰物的表达水平相关。此外，在模拟高海拔（超过 5500 米）低氧缺氧小鼠模型中，随着小鼠外周血和多种组织中缺氧反应的激活，不同 RNA 组的 RNA 修饰丰度在不同组织中发生了敏感变化。RNase 消化实验表明，缺氧暴露下 RNA 修饰丰度的改变影响了组织总 tRNA 富集片段和分离的单个 tRNA 的分子稳定性，如 tRNA、tRNA、tRNA 和 tRNA。体外转染实验表明，从缺氧组转染睾丸总 tRNA 富集片段到 GC-2spd 细胞中，降低了细胞的增殖率，并导致细胞中整体新生蛋白合成减少。
我们的结果表明，不同 RNA 类别的 RNA 修饰在生理条件下的丰度是组织特异性的，并以组织特异性的方式对低氧缺氧暴露做出反应。从机制上讲，低氧缺氧下 tRNA 修饰的失调降低了细胞的增殖率，促进了 tRNA 对 RNase 的敏感性，并导致整体新生蛋白合成减少，这表明 tRNA 表转录组改变在适应环境低氧暴露中的积极作用。
