清华大学沈晓骅团队发现，核RNA稳态促进细胞命运和衰老的系统级协调。2024年4月16日，《细胞—干细胞》杂志在线发表了该研究成果。

利用生长诱导系统，研究人员观察到胚胎干细胞中的RNA外泌体耗竭，会显著影响转录组和蛋白质组，导致多能性丧失和衰老前期的开始。从机理上讲，外泌体耗竭会引发急性核RNA聚集，破坏核RNA-蛋白质平衡。这种干扰限制了核蛋白的可用性，阻碍了聚合酶的启动和参与，从而减少了基因转录。同时，它还会迅速破坏核仁转录、核糖体加工和核输出，导致翻译关闭。

长期的外泌体耗竭会诱发类似衰老细胞的核结构变化，包括染色质异常压实、染色质中心解体和异染色质灶点强化。这些效应表明，核RNA的动态更替协调了重要过程之间的相互影响，从而优化了细胞功能。核RNA稳态的破坏会导致系统功能衰退，改变细胞状态并促进衰老。

据了解，尽管已经了解了单个途径，但了解细胞协调仍然是一项挑战。RNA外泌体靶向多种RNA底物，在细胞衰老过程中经常下调。

附：英文原文

Title: Nuclear RNA homeostasis promotes systems-level coordination of cell fate and senescence

Author: Xue Han, Linqing Xing, Yantao Hong, Xuechun Zhang, Bo Hao, J. Yuyang Lu, Mengyuan Huang, Zuhui Wang, Shaoqian Ma, Ge Zhan, Tong Li, Xiaowen Hao, Yibing Tao, Guanwen Li, Shuqin Zhou, Zheng Zheng, Wen Shao, Yitian Zeng, Dacheng Ma, Wenhao Zhang, Zhen Xie, Haiteng Deng, Jiangwei Yan, Wulan Deng, Xiaohua Shen

Issue&Volume: 2024-04-16

Abstract: Understanding cellular coordination remains a challenge despite knowledge of individualpathways. The RNA exosome, targeting a wide range of RNA substrates, is often downregulatedin cellular senescence. Utilizing an auxin-inducible system, we observed that RNAexosome depletion in embryonic stem cells significantly affects the transcriptomeand proteome, causing pluripotency loss and pre-senescence onset. Mechanistically,exosome depletion triggers acute nuclear RNA aggregation, disrupting nuclear RNA-proteinequilibrium. This disturbance limits nuclear protein availability and hinders polymeraseinitiation and engagement, reducing gene transcription. Concurrently, it promptlydisrupts nucleolar transcription, ribosomal processes, and nuclear exporting, resultingin a translational shutdown. Prolonged exosome depletion induces nuclear structuralchanges resembling senescent cells, including aberrant chromatin compaction, chromocenterdisassembly, and intensified heterochromatic foci. These effects suggest that thedynamic turnover of nuclear RNA orchestrates crosstalk between essential processesto optimize cellular function. Disruptions in nuclear RNA homeostasis result in systemicfunctional decline, altering the cell state and promoting senescence.

DOI: 10.1016/j.stem.2024.03.015

Source: https://www.cell.com/cell-stem-cell/abstract/S1934-5909(24)00096-1