DDX18 coordinates nucleolus phase separation and nuclear organization to control the pluripotency of human embryonic stem cells

Xianle Shi, Yanjing Li, Hongwei Zhou, Xiukun Hou, Jihong Yang, Vikas Malik, Francesco Faiola, Junjun Ding, Xichen Bao, Miha Modic, Weiyu Zhang, Lingyi Chen, Syed Raza Mahmood, Effie Apostolou, Feng-Chun Yang, Mingjiang Xu, Wei Xie, Xin Huang, Yong Chen () and Jianlong Wang ()
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Xianle Shi: Columbia University Irving Medical Center
Yanjing Li: Chinese Academy of Sciences
Hongwei Zhou: Columbia University Irving Medical Center
Xiukun Hou: Tianjin Medical University Cancer Institute and Hospital
Jihong Yang: Columbia University Irving Medical Center
Vikas Malik: Columbia University Irving Medical Center
Francesco Faiola: Icahn School of Medicine at Mount Sinai
Junjun Ding: Icahn School of Medicine at Mount Sinai
Xichen Bao: Chinese Academy of Sciences
Miha Modic: The Francis Crick Institute and University College London
Weiyu Zhang: Nankai University
Lingyi Chen: Nankai University
Syed Raza Mahmood: Weill Cornell Medicine
Effie Apostolou: Weill Cornell Medicine
Feng-Chun Yang: University of Texas Health Science Center at San Antonio
Mingjiang Xu: University of Texas Health Science Center at San Antonio
Wei Xie: Tsinghua University
Xin Huang: Columbia University Irving Medical Center
Yong Chen: Chinese Academy of Sciences
Jianlong Wang: Columbia University Irving Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Pluripotent stem cells possess a unique nuclear architecture characterized by a larger nucleus and more open chromatin, which underpins their ability to self-renew and differentiate. Here, we show that the nucleolus-specific RNA helicase DDX18 is essential for maintaining the pluripotency of human embryonic stem cells. Using techniques such as Hi-C, DNA/RNA-FISH, and biomolecular condensate analysis, we demonstrate that DDX18 regulates nucleolus phase separation and nuclear organization by interacting with NPM1 in the granular nucleolar component, driven by specific nucleolar RNAs. Loss of DDX18 disrupts nucleolar substructures, impairing centromere clustering and perinucleolar heterochromatin (PNH) formation. To probe this further, we develop NoCasDrop, a tool enabling precise nucleolar targeting and controlled liquid condensation, which restores centromere clustering and PNH integrity while modulating developmental gene expression. This study reveals how nucleolar phase separation dynamics govern chromatin organization and cell fate, offering fresh insights into the molecular regulation of stem cell pluripotency.

Date: 2024
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DOI: 10.1038/s41467-024-55054-8

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