The regulatory architecture of the primed pluripotent cell state
Abstract Despite extensive research, the gene regulatory architecture governing mammalian cell states remains poorly understood. Here we present an integrative systems biology approach to elucidate the network architecture of primed state pluripotency. Using an unbiased methodology, we identified an...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2025-04-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57894-4 |
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| author | Bo I. Li Mariano J. Alvarez Hui Zhao Napon Chirathivat Andrea Califano Michael M. Shen |
| author_facet | Bo I. Li Mariano J. Alvarez Hui Zhao Napon Chirathivat Andrea Califano Michael M. Shen |
| author_sort | Bo I. Li |
| collection | DOAJ |
| description | Abstract Despite extensive research, the gene regulatory architecture governing mammalian cell states remains poorly understood. Here we present an integrative systems biology approach to elucidate the network architecture of primed state pluripotency. Using an unbiased methodology, we identified and experimentally confirmed 132 transcription factors as master regulators (MRs) of mouse epiblast stem cell (EpiSC) pluripotency, many of which were further validated by CRISPR-mediated functional assays. To assemble a comprehensive regulatory network, we silenced each of the 132 MRs to assess their effects on the other MRs and their transcriptional targets, yielding a network of 1273 MR → MR interactions. Network architecture analyses revealed four functionally distinct MR modules (communities), and identified key Speaker and Mediator MRs based on their hierarchical rank and centrality. Our findings elucidate the de-centralized logic of a “communal interaction” model in which the balanced activities of four MR communities maintain primed state pluripotency. |
| format | Article |
| id | doaj-art-a2eaf6f64f41436cb99126d62e4e18cc |
| institution | OA Journals |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-a2eaf6f64f41436cb99126d62e4e18cc2025-08-20T02:11:47ZengNature PortfolioNature Communications2041-17232025-04-0116111910.1038/s41467-025-57894-4The regulatory architecture of the primed pluripotent cell stateBo I. Li0Mariano J. Alvarez1Hui Zhao2Napon Chirathivat3Andrea Califano4Michael M. Shen5Department of MedicineSystems BiologyDepartment of MedicineDepartment of MedicineDepartment of MedicineDepartment of MedicineAbstract Despite extensive research, the gene regulatory architecture governing mammalian cell states remains poorly understood. Here we present an integrative systems biology approach to elucidate the network architecture of primed state pluripotency. Using an unbiased methodology, we identified and experimentally confirmed 132 transcription factors as master regulators (MRs) of mouse epiblast stem cell (EpiSC) pluripotency, many of which were further validated by CRISPR-mediated functional assays. To assemble a comprehensive regulatory network, we silenced each of the 132 MRs to assess their effects on the other MRs and their transcriptional targets, yielding a network of 1273 MR → MR interactions. Network architecture analyses revealed four functionally distinct MR modules (communities), and identified key Speaker and Mediator MRs based on their hierarchical rank and centrality. Our findings elucidate the de-centralized logic of a “communal interaction” model in which the balanced activities of four MR communities maintain primed state pluripotency.https://doi.org/10.1038/s41467-025-57894-4 |
| spellingShingle | Bo I. Li Mariano J. Alvarez Hui Zhao Napon Chirathivat Andrea Califano Michael M. Shen The regulatory architecture of the primed pluripotent cell state Nature Communications |
| title | The regulatory architecture of the primed pluripotent cell state |
| title_full | The regulatory architecture of the primed pluripotent cell state |
| title_fullStr | The regulatory architecture of the primed pluripotent cell state |
| title_full_unstemmed | The regulatory architecture of the primed pluripotent cell state |
| title_short | The regulatory architecture of the primed pluripotent cell state |
| title_sort | regulatory architecture of the primed pluripotent cell state |
| url | https://doi.org/10.1038/s41467-025-57894-4 |
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