PT  - JOURNAL ARTICLE
AU  - Sheila Q. Xie
AU  - Bryony J. Leeke
AU  - Chad Whidling
AU  - Ryan T. Wagner
AU  - Ferran Garcia-Llagostera
AU  - Paul Chammas
AU  - Nathan T-F. Cheung
AU  - Dirk Dormann
AU  - Michael T. McManus
AU  - Michelle Percharde
TI  - Nucleolar-based <em>Dux</em> repression is essential for 2-cell stage exit
AID  - 10.1101/2021.11.11.468235
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.11.11.468235
4099  - http://biorxiv.org/content/early/2021/11/12/2021.11.11.468235.short
4100  - http://biorxiv.org/content/early/2021/11/12/2021.11.11.468235.full
AB  - 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 StatementThe authors have declared no competing interest.