DDX18 coordinates nucleolus phase separation and nuclear organization to control the pluripotency of human embryonic stem cells
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 o...
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Nature Portfolio
2024-12-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55054-8 |
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| author | 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 Jianlong Wang |
| author_facet | 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 Jianlong Wang |
| author_sort | Xianle Shi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4ba914ce7f2f44e38daffb5c8980eef8 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-4ba914ce7f2f44e38daffb5c8980eef82025-01-05T12:35:48ZengNature PortfolioNature Communications2041-17232024-12-0115112110.1038/s41467-024-55054-8DDX18 coordinates nucleolus phase separation and nuclear organization to control the pluripotency of human embryonic stem cellsXianle Shi0Yanjing Li1Hongwei Zhou2Xiukun Hou3Jihong Yang4Vikas Malik5Francesco Faiola6Junjun Ding7Xichen Bao8Miha Modic9Weiyu Zhang10Lingyi Chen11Syed Raza Mahmood12Effie Apostolou13Feng-Chun Yang14Mingjiang Xu15Wei Xie16Xin Huang17Yong Chen18Jianlong Wang19Department of Medicine, Columbia Center for Human Development and Stem Cell Therapies, Columbia University Irving Medical CenterShanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of SciencesDepartment of Medicine, Columbia Center for Human Development and Stem Cell Therapies, Columbia University Irving Medical CenterDepartment of Thyroid and Neck Cancer, Tianjin Medical University Cancer Institute and HospitalDepartment of Medicine, Columbia Center for Human Development and Stem Cell Therapies, Columbia University Irving Medical CenterDepartment of Medicine, Columbia Center for Human Development and Stem Cell Therapies, Columbia University Irving Medical CenterBlack Family Stem Cell Institute, Icahn School of Medicine at Mount SinaiBlack Family Stem Cell Institute, Icahn School of Medicine at Mount SinaiGuangzhou Institutes of Biomedicine and Health, Chinese Academy of SciencesThe Francis Crick Institute and University College LondonCollege of Life Sciences, Nankai UniversityCollege of Life Sciences, Nankai UniversityDepartment of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell MedicineDepartment of Medicine, Sandra and Edward Meyer Cancer Center, Weill Cornell MedicineDepartment of Molecular Medicine/Cell Systems and Anatomy, University of Texas Health Science Center at San AntonioDepartment of Molecular Medicine/Cell Systems and Anatomy, University of Texas Health Science Center at San AntonioSchool of Life Sciences, Tsinghua UniversityDepartment of Medicine, Columbia Center for Human Development and Stem Cell Therapies, Columbia University Irving Medical CenterShanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of SciencesDepartment of Medicine, Columbia Center for Human Development and Stem Cell Therapies, Columbia University Irving Medical CenterAbstract 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.https://doi.org/10.1038/s41467-024-55054-8 |
| spellingShingle | 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 Jianlong Wang DDX18 coordinates nucleolus phase separation and nuclear organization to control the pluripotency of human embryonic stem cells Nature Communications |
| title | DDX18 coordinates nucleolus phase separation and nuclear organization to control the pluripotency of human embryonic stem cells |
| title_full | DDX18 coordinates nucleolus phase separation and nuclear organization to control the pluripotency of human embryonic stem cells |
| title_fullStr | DDX18 coordinates nucleolus phase separation and nuclear organization to control the pluripotency of human embryonic stem cells |
| title_full_unstemmed | DDX18 coordinates nucleolus phase separation and nuclear organization to control the pluripotency of human embryonic stem cells |
| title_short | DDX18 coordinates nucleolus phase separation and nuclear organization to control the pluripotency of human embryonic stem cells |
| title_sort | ddx18 coordinates nucleolus phase separation and nuclear organization to control the pluripotency of human embryonic stem cells |
| url | https://doi.org/10.1038/s41467-024-55054-8 |
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