rRNA biogenesis regulates mouse 2C-like state by 3D structure reorganization of peri-nucleolar heterochromatin.
rRNA biogenesis regulates mouse 2C-like state by 3D structure reorganization of peri-nucleolar heterochromatin.
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rRNA生物发生通过核仁周围异染色质的3D结构重组调节小鼠2C样状态
DOI：
10.1038/s41467-021-26576-2
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发表时间：
2021-11-09
影响因子：
16.6
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Yu H;Sun Z;Tan T;Pan H;Zhao J;Zhang L;Chen J;Lei A;Zhu Y;Chen L;Xu Y;Liu Y;Chen M;Sheng J;Xu Z;Qian P;Li C;Gao S;Daley GQ;Zhang J
核仁是核糖体生物发生和感知各种压力的细胞器。然而，其在调节干细胞命运中的作用仍不清楚。在这里，我们提出的证据表明，干扰 rRNA 生物发生诱导的核仁应激可以驱动 2 细胞阶段胚胎样 (2C 样) 程序，并诱导小鼠胚胎干 (mES) 细胞中扩大 2C 样细胞群。从机制上讲，核仁完整性维持核仁正常的液-液相分离（LLPS）和核仁周围异染色质（PNH）的形成。 rRNA生物发生缺陷时，核仁LLPS的自然状态被破坏，导致NCL/TRIM28复合物从PNH解离，表观遗传状态发生变化，PNH 3D结构重组，导致PNH释放2C程序转录因子Dux，激活类似2C的程序。相应地，具有 rRNA 生物发生缺陷的胚胎无法从 2 细胞 (2C) 发育为 4 细胞胚胎，2C/ERV 基因延迟抑制，转录组偏向早期卵裂胚胎特征。我们的结果强调，rRNA 介导的核仁完整性和 PNH 区室的 3D 结构重塑调节 mES 细胞向 2C 样细胞的命运转变，并且 rRNA 生物发生是小鼠植入前胚胎发育的 2 细胞到 4 细胞转变过程中的关键调节因子。
The nucleolus is the organelle for ribosome biogenesis and sensing various types of stress. However, its role in regulating stem cell fate remains unclear. Here, we present evidence that nucleolar stress induced by interfering rRNA biogenesis can drive the 2-cell stage embryo-like (2C-like) program and induce an expanded 2C-like cell population in mouse embryonic stem (mES) cells. Mechanistically, nucleolar integrity maintains normal liquid-liquid phase separation (LLPS) of the nucleolus and the formation of peri-nucleolar heterochromatin (PNH). Upon defects in rRNA biogenesis, the natural state of nucleolus LLPS is disrupted, causing dissociation of the NCL/TRIM28 complex from PNH and changes in epigenetic state and reorganization of the 3D structure of PNH, which leads to release of Dux, a 2C program transcription factor, from PNH to activate a 2C-like program. Correspondingly, embryos with rRNA biogenesis defect are unable to develop from 2-cell (2C) to 4-cell embryos, with delayed repression of 2C/ERV genes and a transcriptome skewed toward earlier cleavage embryo signatures. Our results highlight that rRNA-mediated nucleolar integrity and 3D structure reshaping of the PNH compartment regulates the fate transition of mES cells to 2C-like cells, and that rRNA biogenesis is a critical regulator during the 2-cell to 4-cell transition of murine pre-implantation embryo development.