Nuclear RNA homeostasis promotes systems-level coordination of cell fate and senescence
Cell Stem Cell. 2024 Apr 12:S1934-5909(24)00096-1. doi: 10.1016/j.stem.2024.03.015. Online ahead of print.ABSTRACTUnderstanding cellular coordination remains a challenge despite knowledge of individual pathways. The RNA exosome, targeting a wide range of RNA substrates, is often downregulated in cellular senescence. Utilizing an auxin-inducible system, we observed that RNA exosome depletion in embryonic stem cells significantly affects the transcriptome and proteome, causing pluripotency loss and pre-senescence onset. Mechanistically, exosome depletion triggers acute nuclear RNA aggregation, disrupting nuclear RNA-protein equilibrium. This disturbance limits nuclear protein availability and hinders polymerase initiation and engagement, reducing gene transcription. Concurrently, it promptly disrupts nucleolar transcription, ribosomal processes, and nuclear exporting, resulting in a translational shutdown. Prolonged exosome depletion induces nuclear structural changes resembling senescent cells, including aberrant chromatin compaction, chromocenter disassembly, and intensified heterochromatic foci. These effects suggest that the dynamic turnover of nuclear RNA orchestrates crosstalk between essential processes to optimize cellular function. Disruptions in nuclear RNA homeostasis result in systemic functional decline, altering the cell state and promoting senescence.PMID:38631356 | DOI:10.1016/j.stem.2024.03.015
Source: Cell Stem Cell - Category: Stem Cells Authors: 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 Y Source Type: research