LIN28 coordinately promotes nucleolar/ribosomal functions and represses the 2C-like transcriptional program in pluripotent stem cells.
LIN28 coordinately promotes nucleolar/ribosomal functions and represses the 2C-like transcriptional program in pluripotent stem cells.
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LIN28协调促进核仁/核糖体功能并抑制多能干细胞中的2C样转录程序
DOI：
10.1007/s13238-021-00864-5
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发表时间：
2022-07
期刊：
影响因子：
21.1
通讯作者：
Zhang, Jin
中科院分区：
文献类型：
--
作者：
Sun, Zhen;Yu, Hua;Zhao, Jing;Tan, Tianyu;Pan, Hongru;Zhu, Yuqing;Chen, Lang;Zhang, Cheng;Zhang, Li;Lei, Anhua;Xu, Yuyan;Bi, Xianju;Huang, Xin;Gao, Bo;Wang, Longfei;Correia, Cristina;Chen, Ming;Sun, Qiming;Feng, Yu;Shen, Li;Wu, Hao;Wang, Jianlong;Shen, Xiaohua;Daley, George Q.;Li, Hu;Zhang, Jin
LIN28 是一种 RNA 结合蛋白，在早期胚胎发育、干细胞分化/重编程、肿瘤发生和代谢中发挥重要作用。之前的研究主要集中在它在细胞质中与 Let-7microRNA 前体或 mRNA 相互作用的作用，很少涉及 LIN28 在细胞核内的作用。在这里，我们证明 LIN28 在小鼠胚胎发育过程中表现出动态的时间和空间表达。母体 LIN28 表达在退出 2 细胞阶段后下降，而合子 LIN28 蛋白在 4 细胞至囊胚阶段发育过程中在形成核仁处被诱导，在植入后在细胞质中显性表达。在培养的多能干细胞 (PSC) 中，LIN28 的缺失会导致核仁应激并激活以内源逆转录病毒基因表达为特征的 2 细胞/4 细胞样转录程序。从机制上讲，LIN28 与小核仁 RNA 和 rRNA 结合以维持核仁完整性，其丢失会导致核仁相分离缺陷、核糖体应激和 P53 激活，而 P53 反过来又与 2C 转录因子 Dux 结合并激活。 LIN28 还存在于含有核仁因子 Nucleolin (NCL) 和转录抑制子 TRIM28 的复合物中，LIN28 缺失导致 NCL/TRIM28 复合物在 Dux 和 rDNA 位点上的占据减少，从而解除 Dux 的抑制并减少 rRNA 表达。具有核仁应激的 Lin28 敲除细胞更有可能呈现缓慢循环、翻译惰性和合成代谢的状态。非活动状态，这是以前未受重视的类 2C 转录程序的一部分。这些发现阐明了核仁 LIN28 在 PSC 中的新作用，以及将 2C 程序与 PSC 和早期胚胎发育中的核仁功能联系起来的新机制。
LIN28 is an RNA binding protein with important roles in early embryo development, stem cell differentiation/reprogramming, tumorigenesis and metabolism. Previous studies have focused mainly on its role in the cytosol where it interacts withLet-7microRNA precursors or mRNAs, and few have addressed LIN28's role within the nucleus. Here, we show that LIN28 displays dynamic temporal and spatial expression during murine embryo development. Maternal LIN28 expression drops upon exit from the 2-cell stage, and zygotic LIN28 protein is induced at the forming nucleolus during 4-cell to blastocyst stage development, to become dominantly expressed in the cytosol after implantation. In cultured pluripotent stem cells (PSCs), loss of LIN28 led to nucleolar stress and activation of a 2-cell/4-cell-like transcriptional program characterized by the expression of endogenous retrovirus genes. Mechanistically, LIN28 binds to small nucleolar RNAs and rRNA to maintain nucleolar integrity, and its loss leads to nucleolar phase separation defects, ribosomal stress and activation of P53 which in turn binds to and activates 2C transcription factorDux. LIN28 also resides in a complex containing the nucleolar factor Nucleolin (NCL) and the transcriptional repressor TRIM28, and LIN28 loss leads to reduced occupancy of the NCL/TRIM28 complex on theDuxand rDNA loci, and thus de-repressedDuxand reduced rRNA expression.Lin28knockout cells with nucleolar stress are more likely to assume a slowly cycling, translationally inert and anabolically inactive state, which is a part of previously unappreciated 2C-like transcriptional program. These findings elucidate novel roles for nucleolar LIN28 in PSCs, and a new mechanism linking 2C program and nucleolar functions in PSCs and early embryo development.
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