lncRNAs 的不同处理有助于干细胞中非保守功能的发挥。

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

机构信息

State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.

CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, University of the Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.

出版信息

Cell. 2020 Apr 30;181(3):621-636.e22. doi: 10.1016/j.cell.2020.03.006. Epub 2020 Apr 6.

DOI:10.1016/j.cell.2020.03.006

PMID:32259487

Abstract

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.

摘要

长非编码 RNA（lncRNA）的进化速度快于 mRNA。保守的 lncRNA 是否经历保守的加工、定位和功能仍然未知。我们报告了人胚胎干细胞（hESC）和小鼠胚胎干细胞（mESC）中 lncRNA 的不同亚细胞定位。hESC 中定位于细胞质的 lncRNA 比例明显高于 mESC。这对于 hESC 多能性很重要。FAST 是一个位置保守的 lncRNA，但在其加工和定位上并不保守。在 hESC 中，细胞质定位的 hFAST 与 E3 泛素连接酶 β-TrCP 的 WD40 结构域结合，并阻止其与磷酸化的 β-catenin 相互作用，从而阻止降解，导致 WNT 信号激活，这是多能性所必需的。相比之下，mFast 在 mESC 中保留在核内，其加工受到剪接因子 PPIE 的抑制，PPIE 在 mESC 中高度表达，但在 hESC 中不表达。这些发现揭示了 lncRNA 加工和定位是功能快速进化的先前未被充分认识的贡献因素。