rRNA biogenesis regulates mouse 2C-like state by 3D structure reorganization of peri-nucleolar heterochromatin

Hua Yu, Zhen Sun, Tianyu Tan, Hongru Pan, Jing Zhao, Ling Zhang, Jiayu Chen, Anhua Lei, Yuqing Zhu, Lang Chen, Yuyan Xu, Yaxin Liu, Ming Chen, Jinghao Sheng, Zhengping Xu, Pengxu Qian, Cheng Li, Shaorong Gao, George Q. Daley and Jin Zhang ()
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Hua Yu: Zhejiang University School of Medicine
Zhen Sun: Zhejiang University School of Medicine
Tianyu Tan: Zhejiang University School of Medicine
Hongru Pan: Zhejiang University School of Medicine
Jing Zhao: Zhejiang University School of Medicine
Ling Zhang: Zhejiang University School of Medicine
Jiayu Chen: Tongji University
Anhua Lei: Zhejiang University School of Medicine
Yuqing Zhu: Zhejiang University School of Medicine
Lang Chen: Zhejiang University School of Medicine
Yuyan Xu: Zhejiang University School of Medicine
Yaxin Liu: Zhejiang University School of Medicine
Ming Chen: Zhejiang University
Jinghao Sheng: Zhejiang University School of Medicine
Zhengping Xu: Zhejiang University School of Medicine
Pengxu Qian: Zhejiang University School of Medicine
Cheng Li: Peking University
Shaorong Gao: Tongji University
George Q. Daley: Harvard Medical School
Jin Zhang: Zhejiang University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-21

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-26576-2

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