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

Autor: Shi X; Department of Medicine, Columbia Center for Human Development and Stem Cell Therapies, Columbia University Irving Medical Center, New York, NY, USA.; School of Life Sciences, Tsinghua University, Beijing, China., Li Y; Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Shanghai, China., Zhou H; Department of Medicine, Columbia Center for Human Development and Stem Cell Therapies, Columbia University Irving Medical Center, New York, NY, USA., Hou X; Department of Thyroid and Neck Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China., Yang J; Department of Medicine, Columbia Center for Human Development and Stem Cell Therapies, Columbia University Irving Medical Center, New York, NY, USA., Malik V; Department of Medicine, Columbia Center for Human Development and Stem Cell Therapies, Columbia University Irving Medical Center, New York, NY, USA., Faiola F; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Ding J; Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Bao X; Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China., Modic M; The Francis Crick Institute and University College London, London, UK., Zhang W; College of Life Sciences, Nankai University, Tianjin, China., Chen L; College of Life Sciences, Nankai University, Tianjin, China., Mahmood SR; Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA., Apostolou E; Department of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA., Yang FC; Department of Molecular Medicine/Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA., Xu M; Department of Molecular Medicine/Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA., Xie W; School of Life Sciences, Tsinghua University, Beijing, China., Huang X; Department of Medicine, Columbia Center for Human Development and Stem Cell Therapies, Columbia University Irving Medical Center, New York, NY, USA., Chen Y; Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China. yongchen@sibcb.ac.cn., Wang J; Department of Medicine, Columbia Center for Human Development and Stem Cell Therapies, Columbia University Irving Medical Center, New York, NY, USA. jw3925@cumc.columbia.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Dec 30; Vol. 15 (1), pp. 10803. Date of Electronic Publication: 2024 Dec 30.
DOI: 10.1038/s41467-024-55054-8
Abstrakt: 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.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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