Abstract
Upon fertilization, the mammalian embryo must switch from dependence on maternal transcripts to transcribing its own genome, and in mice this involves the transient up-regulation of MERVL transposons and MERVL-driven genes at the two-cell stage. The mechanisms and requirement for MERVL and two-cell (2C) gene up-regulation are poorly understood. Moreover, this MERVL-driven transcriptional program must be rapidly shut off to allow two-cell 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 two-cell embryos show similar immature nucleoli with altered structure and reduced rRNA output. We reveal that nucleolar disruption via blocking RNA polymerase 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 nucleolar maturation and Dux silencing and leads to two- to four-cell arrest. Our findings reveal an intriguing link between rRNA synthesis, nucleolar maturation, and gene repression during early development.
Highlights
Upon fertilization, one of the earliest requirements in the development of a new organism is the formation of a totipotent zygote, which possesses the capacity to generate the entire embryo and all extraembryonic structures
Major ZGA is an essential process occurring at the twocell stage of early mouse embryogenesis, which entails rapid activation of zygotic RNAs required for subsequent development
We reveal that high ribosomal RNA (rRNA) synthesis and nucleolar maturation from inactive nucleolar precursor bodies (NPBs) are essential drivers of Dux repression in embryos and 2C-like cells
Summary
One of the earliest requirements in the development of a new organism is the formation of a totipotent zygote, which possesses the capacity to generate the entire embryo and all extraembryonic structures. GENES & DEVELOPMENT 36:1–17 Published by Cold Spring Harbor Laboratory Press; ISSN 0890-9369/22; www.genesdev.org population of cells within ESC cultures that share several epigenetic, metabolic, and transcriptomic features with two-cell embryos, termed two-cell (2C)-like cells (Macfarlan et al 2012; Bošković et al 2014), marked by expression of a MERVL-GFP (2C-GFP) reporter. This tool recently led to the discovery of Dux (DUX4 in humans) as a potent MERVL/HERVL and 2C activator. The mechanisms for such rapid shutdown of Dux and MERVL gene expression at the late two-cell stage are unclear
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