Distinct Processing of lncRNAs Contributes to Non-conserved Functions in Stem Cells

• Published in: Cell 2020-04, Vol.181 (3), p.621-636.e22
• Main Authors: Guo, Chun-Jie, Ma, Xu-Kai, Xing, Yu-Hang, Zheng, Chuan-Chuan, Xu, Yi-Feng, Shan, Lin, Zhang, Jun, Wang, Shaohua, Wang, Yangming, Carmichael, Gordon G., Yang, Li, Chen, Ling-Ling
• Format: Article
• Language: English
• Subjects: Animals; beta catenin; Cell Differentiation - genetics; Cell Line; Cells, Cultured; conservation; cytoplasm; embryonic stem cell; embryonic stem cells; Embryonic Stem Cells - metabolism; ESC; evolution; FAST; Human Embryonic Stem Cells - metabolism; Humans; Intracellular Space - genetics; lncRNA; long noncoding RNA; messenger RNA; Mice; Mouse Embryonic Stem Cells - metabolism; non-coding RNA; PPIE; RNA processing; RNA Splicing - genetics; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; RNA, Messenger - metabolism; Signal Transduction - genetics; splicing; Stem Cells - metabolism; Stem Cells - pathology; subcellular localization; ubiquitin-protein ligase; WNT
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2020.03.006

Long noncoding RNAs (lncRNAs) evolve more rapidly than mRNAs. Whether conserved lncRNAs undergo conserved processing, localization, and function remains unexplored. We report differing subcellular localization of lncRNAs in human and mouse embryonic stem cells (ESCs). A significantly higher fraction of lncRNAs is localized in the cytoplasm of hESCs than in mESCs. This turns out to be important for hESC pluripotency. FAST is a positionally conserved lncRNA but is not conserved in its processing and localization. In hESCs, cytoplasm-localized hFAST binds to the WD40 domain of the E3 ubiquitin ligase β-TrCP and blocks its interaction with phosphorylated β-catenin to prevent degradation, leading to activated WNT signaling, required for pluripotency. In contrast, mFast is nuclear retained in mESCs, and its processing is suppressed by the splicing factor PPIE, which is highly expressed in mESCs but not hESCs. These findings reveal that lncRNA processing and localization are previously under-appreciated contributors to the rapid evolution of function. [Display omitted] •Subcellular localization of conserved lncRNAs is different in hESCs and mESCs•Cytoplasmic hFAST but not nuclear mFast promotes WNT signaling in hESC pluripotency•PPIE regulates distinct FAST processing in hESCs and mESCs•RNA processing and localization contribute to lncRNA functional evolution A pair of lncRNA orthologs exhibits different subcellular localization in human and murine ESCs because of differential RNA processing, which, in turn, leads to their functional divergence in the context of pluripotency regulation. The findings highlight how conserved lncRNAs may achieve functional evolution through non-conserved RNA processing.