Regulation and Roles of the Nucleolus in Embryonic Stem Cells: From Ribosome Biogenesis to Genome Organization

Abstract

The nucleolus is the largest compartment of the eukaryotic cell's nucleus. It acts as a ribosome factory, thereby sustaining the translation machinery. The nucleolus is also the subnuclear compartment with the highest transcriptional activity in the cell, where hundreds of ribosomal RNA (rRNA) genes transcribe the overwhelming majority of RNAs. The structure and composition of the nucleolus change according to the developmental state. For instance, in embryonic stem cells (ESCs), rRNA genes display a hyperactive transcriptional state and open chromatin structure compared with differentiated cells. Increasing evidence indicates that the role of the nucleolus and rRNA genes might go beyond the control of ribosome biogenesis. One such role is linked to the genome architecture, since repressive domains are often located close to the nucleolus. This review highlights recent findings describing how the nucleolus is regulated in ESCs and its role in regulating ribosome biogenesis and genome organization for the maintenance of stem cell identity.

The human ribosomal RNA gene is composed of highly homogenized tandem clusters

“…Next, we analyzed rDNA methylation status in human induced pluripotent stem cells (hiPSCs, 201B7) by Cas9-enriched sequencing. In ESCs and iPSCs, rDNA is thought to be globally unmethylated because of the high transcription activity (Gupta and Santoro 2020). Unexpectedly, however, around half of the 45S rDNAs were methylated and the IGS was heavily methylated in the iPSCs, similar to differentiated cells (Fig.…”

“…Lastly, regarding the methylation in ES and iPS cells, the results differed between human and mouse. We expected that both cell types would be less methylated than their differentiated counterparts because the nucleolus of ES and iPS cells is known to be larger and rRNA transcription activity is high (Woolnough et al 2016; Gupta and Santoro 2020; Wang and Lemos 2019). In the human iPSC and ESCs, however, the methylation status of the 45S rDNA was similar to that in differentiated cells.…”

Genome-wide maps of nucleolus interactions reveal distinct layers of repressive chromatin domains

“…The nucleolus is the largest compartment of the eukaryotic cell’s nucleus, known to act as a ribosome factory, thereby sustaining the translation machinery for protein synthesis (Gupta and Santoro, 2020). Increasing evidence indicates that the role of the nucleolus and rRNA genes might go beyond the control of ribosome biogenesis.…”

“…These results support a role of the nucleolus in establishing repressive chromatin states at regions close to the nucleolus. It is important here to note that in ESCs all rRNA genes are transcriptionally and epigenetically active compared to differentiated cells and this state is required to maintain pluripotency (reviewed in (Gupta and Santoro, 2020). However, this hyperactive state of rRNA genes in ESCs does not positively correlate with elevated protein synthesis relative to differentiated cells (Guzzi et al, 2018; Ingolia et al, 2011; Sampath et al, 2008).…”

The mystery of monozygotic twinning II: What can monozygotic twinning tell us about Amyoplasia from a review of the various mechanisms and types of monozygotic twinning?

“…Reversing endoplasmic reticulum stress may also be important for ova survival (Song et al, 2012). The nucleolus and its role in ribosome production could be key (Gupta & Santoro, 2020). In animals, certain treatment of the “overripe ova” and dying cells seems to increase the viability of the embryo (Jiang et al, 2019; Kim et al, 2019; Lin et al, 2018; Park et al, 2019; Zhang et al, 2018, 2019).…”