RT Journal Article SR Electronic T1 Nucleolar-based Dux repression is essential for 2-cell stage exit JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.11.11.468235 DO 10.1101/2021.11.11.468235 A1 Sheila Q. Xie A1 Bryony J. Leeke A1 Chad Whidling A1 Ryan T. Wagner A1 Ferran Garcia-Llagostera A1 Paul Chammas A1 Nathan T-F. Cheung A1 Dirk Dormann A1 Michael T. McManus A1 Michelle Percharde YR 2021 UL http://biorxiv.org/content/early/2021/11/12/2021.11.11.468235.abstract 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.