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Nucleolar-based Dux repression is essential for 2-cell stage exit

Sheila Q. Xie, Bryony J. Leeke, Chad Whidling, Ryan T. Wagner, Ferran Garcia-Llagostera, Paul Chammas, Nathan T-F. Cheung, Dirk Dormann, Michael T. McManus, Michelle Percharde
doi: https://doi.org/10.1101/2021.11.11.468235
Sheila Q. Xie
1MRC London Institute of Medical Sciences, Du Cane Road, London, UK
2Institute of Clinical Sciences, Imperial College London, Du Cane Road, London, UK
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Bryony J. Leeke
1MRC London Institute of Medical Sciences, Du Cane Road, London, UK
2Institute of Clinical Sciences, Imperial College London, Du Cane Road, London, UK
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Chad Whidling
1MRC London Institute of Medical Sciences, Du Cane Road, London, UK
2Institute of Clinical Sciences, Imperial College London, Du Cane Road, London, UK
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Ryan T. Wagner
3University of California San Francisco, Parnassus Avenue, San Francisco, USA
4Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, USA
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Ferran Garcia-Llagostera
1MRC London Institute of Medical Sciences, Du Cane Road, London, UK
2Institute of Clinical Sciences, Imperial College London, Du Cane Road, London, UK
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Paul Chammas
1MRC London Institute of Medical Sciences, Du Cane Road, London, UK
2Institute of Clinical Sciences, Imperial College London, Du Cane Road, London, UK
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Nathan T-F. Cheung
1MRC London Institute of Medical Sciences, Du Cane Road, London, UK
2Institute of Clinical Sciences, Imperial College London, Du Cane Road, London, UK
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Dirk Dormann
1MRC London Institute of Medical Sciences, Du Cane Road, London, UK
2Institute of Clinical Sciences, Imperial College London, Du Cane Road, London, UK
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Michael T. McManus
3University of California San Francisco, Parnassus Avenue, San Francisco, USA
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Michelle Percharde
1MRC London Institute of Medical Sciences, Du Cane Road, London, UK
2Institute of Clinical Sciences, Imperial College London, Du Cane Road, London, UK
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  • For correspondence: m.percharde@lms.mrc.ac.uk
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Abstract

Upon fertilisation, the mammalian embryo must switch from dependence on maternal transcripts to transcribing its own genome, and in mice involves the transient upregulation of MERVL transposons and MERVL-driven genes at the 2-cell stage. The mechanisms and requirement for MERVL and 2-cell (2C) gene upregulation are poorly understood. Moreover, this MERVL-driven transcriptional program must be rapidly shut off to allow 2C exit and developmental progression. Here, we report that robust ribosomal RNA (rRNA) synthesis and nucleolar maturation are essential for exit from the 2C state. 2C-like cells and 2C embryos show similar immature nucleoli with altered structure and reduced rRNA output. We reveal that nucleolar disruption via blocking Pol I activity or preventing nucleolar phase separation enhances conversion to a 2C-like state in embryonic stem cells (ESCs) by detachment of the MERVL activator Dux from the nucleolar surface. In embryos, nucleolar disruption prevents proper Dux silencing and leads to 2-4 cell arrest. Our findings reveal an intriguing link between rRNA synthesis, nucleolar maturation and gene repression during early development.

Competing Interest Statement

The authors have declared no competing interest.

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Posted November 12, 2021.
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Nucleolar-based Dux repression is essential for 2-cell stage exit
Sheila Q. Xie, Bryony J. Leeke, Chad Whidling, Ryan T. Wagner, Ferran Garcia-Llagostera, Paul Chammas, Nathan T-F. Cheung, Dirk Dormann, Michael T. McManus, Michelle Percharde
bioRxiv 2021.11.11.468235; doi: https://doi.org/10.1101/2021.11.11.468235
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Nucleolar-based Dux repression is essential for 2-cell stage exit
Sheila Q. Xie, Bryony J. Leeke, Chad Whidling, Ryan T. Wagner, Ferran Garcia-Llagostera, Paul Chammas, Nathan T-F. Cheung, Dirk Dormann, Michael T. McManus, Michelle Percharde
bioRxiv 2021.11.11.468235; doi: https://doi.org/10.1101/2021.11.11.468235

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