CNOT3-Dependent mRNA Deadenylation Safeguards the Pluripotent State
Poly(A) tail length and mRNA deadenylation play important roles in gene regulation. However, how they regulate embryonic development and pluripotent cell fate is not fully understood. Here we present evidence that CNOT3-dependent mRNA deadenylation governs the pluripotent state. We show that CNOT3,...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2016-11-01
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| Series: | Stem Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213671116302132 |
| _version_ | 1818848808562327552 |
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| author | Xiaofeng Zheng Pengyi Yang Brad Lackford Brian D. Bennett Li Wang Hui Li Yu Wang Yiliang Miao Julie F. Foley David C. Fargo Ying Jin Carmen J. Williams Raja Jothi Guang Hu |
| author_facet | Xiaofeng Zheng Pengyi Yang Brad Lackford Brian D. Bennett Li Wang Hui Li Yu Wang Yiliang Miao Julie F. Foley David C. Fargo Ying Jin Carmen J. Williams Raja Jothi Guang Hu |
| author_sort | Xiaofeng Zheng |
| collection | DOAJ |
| description | Poly(A) tail length and mRNA deadenylation play important roles in gene regulation. However, how they regulate embryonic development and pluripotent cell fate is not fully understood. Here we present evidence that CNOT3-dependent mRNA deadenylation governs the pluripotent state. We show that CNOT3, a component of the Ccr4-Not deadenylase complex, is required for mouse epiblast maintenance. It is highly expressed in blastocysts and its deletion leads to peri-implantation lethality. The epiblast cells in Cnot3 deletion embryos are quickly lost during diapause and fail to outgrow in culture. Mechanistically, CNOT3 C terminus is required for its interaction with the complex and its function in embryonic stem cells (ESCs). Furthermore, Cnot3 deletion results in increases in the poly(A) tail lengths, half-lives, and steady-state levels of differentiation gene mRNAs. The half-lives of CNOT3 target mRNAs are shorter in ESCs and become longer during normal differentiation. Together, we propose that CNOT3 maintains the pluripotent state by promoting differentiation gene mRNA deadenylation and degradation, and we identify poly(A) tail-length regulation as a post-transcriptional mechanism that controls pluripotency. |
| first_indexed | 2024-12-19T06:23:14Z |
| format | Article |
| id | doaj.art-5e00422cd03e49909d44be40876f4591 |
| institution | Directory Open Access Journal |
| issn | 2213-6711 |
| language | English |
| last_indexed | 2024-12-19T06:23:14Z |
| publishDate | 2016-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Reports |
| spelling | doaj.art-5e00422cd03e49909d44be40876f45912022-12-21T20:32:38ZengElsevierStem Cell Reports2213-67112016-11-017589791010.1016/j.stemcr.2016.09.007CNOT3-Dependent mRNA Deadenylation Safeguards the Pluripotent StateXiaofeng Zheng0Pengyi Yang1Brad Lackford2Brian D. Bennett3Li Wang4Hui Li5Yu Wang6Yiliang Miao7Julie F. Foley8David C. Fargo9Ying Jin10Carmen J. Williams11Raja Jothi12Guang Hu13Epigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USAEpigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USAEpigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USAIntegrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USAEpigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USALaboratory of Molecular Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaCellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USAReproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USACellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USAIntegrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USALaboratory of Molecular Developmental Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaReproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USAEpigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USAEpigenetics and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USAPoly(A) tail length and mRNA deadenylation play important roles in gene regulation. However, how they regulate embryonic development and pluripotent cell fate is not fully understood. Here we present evidence that CNOT3-dependent mRNA deadenylation governs the pluripotent state. We show that CNOT3, a component of the Ccr4-Not deadenylase complex, is required for mouse epiblast maintenance. It is highly expressed in blastocysts and its deletion leads to peri-implantation lethality. The epiblast cells in Cnot3 deletion embryos are quickly lost during diapause and fail to outgrow in culture. Mechanistically, CNOT3 C terminus is required for its interaction with the complex and its function in embryonic stem cells (ESCs). Furthermore, Cnot3 deletion results in increases in the poly(A) tail lengths, half-lives, and steady-state levels of differentiation gene mRNAs. The half-lives of CNOT3 target mRNAs are shorter in ESCs and become longer during normal differentiation. Together, we propose that CNOT3 maintains the pluripotent state by promoting differentiation gene mRNA deadenylation and degradation, and we identify poly(A) tail-length regulation as a post-transcriptional mechanism that controls pluripotency.http://www.sciencedirect.com/science/article/pii/S2213671116302132pluripotent statepre-implantation developmentembryonic stem cellmRNA deadenylation |
| spellingShingle | Xiaofeng Zheng Pengyi Yang Brad Lackford Brian D. Bennett Li Wang Hui Li Yu Wang Yiliang Miao Julie F. Foley David C. Fargo Ying Jin Carmen J. Williams Raja Jothi Guang Hu CNOT3-Dependent mRNA Deadenylation Safeguards the Pluripotent State Stem Cell Reports pluripotent state pre-implantation development embryonic stem cell mRNA deadenylation |
| title | CNOT3-Dependent mRNA Deadenylation Safeguards the Pluripotent State |
| title_full | CNOT3-Dependent mRNA Deadenylation Safeguards the Pluripotent State |
| title_fullStr | CNOT3-Dependent mRNA Deadenylation Safeguards the Pluripotent State |
| title_full_unstemmed | CNOT3-Dependent mRNA Deadenylation Safeguards the Pluripotent State |
| title_short | CNOT3-Dependent mRNA Deadenylation Safeguards the Pluripotent State |
| title_sort | cnot3 dependent mrna deadenylation safeguards the pluripotent state |
| topic | pluripotent state pre-implantation development embryonic stem cell mRNA deadenylation |
| url | http://www.sciencedirect.com/science/article/pii/S2213671116302132 |
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