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Review
. 2019 Jun 12;8(6):579.
doi: 10.3390/cells8060579.

Genome Organization in and around the Nucleolus

Cristiana Bersaglieri  1   2 , Raffaella Santoro  3
Affiliations
Review

Genome Organization in and around the Nucleolus

Cristiana Bersaglieri et al. Cells. .

Abstract

The nucleolus is the largest substructure in the nucleus, where ribosome biogenesis takes place, and forms around the nucleolar organizer regions (NORs) that comprise ribosomal RNA (rRNA) genes. Each cell contains hundreds of rRNA genes, which are organized in three distinct chromatin and transcriptional states-silent, inactive and active. Increasing evidence indicates that the role of the nucleolus and rRNA genes goes beyond the control of ribosome biogenesis. Recent results highlighted the nucleolus as a compartment for the location and regulation of repressive genomic domains and, together with the nuclear lamina, represents the hub for the organization of the inactive heterochromatin. In this review, we aim to describe the crosstalk between the nucleolus and the rest of the genome and how distinct rRNA gene chromatin states affect nucleolus structure and are implicated in genome stability, genome architecture, and cell fate decision.

Keywords: NoRC; Nucleolus; cancer; chromatin; embryonic stem cells; epigenetics; genome architecture; genome instability; lamina-associated domains(LADs); lncRNA; nucleolus-associated domains (NADs); rRNA genes.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The three major classes of rRNA genes. (a) Structural organization of mouse rRNA gene. The sites of transcription initiation of the 45S pre-rRNA from the main gene promoter and IGS-rRNA transcripts from the spacer promoter are indicated by arrows. Terminator elements downstream of the spacer promoter (T-1), upstream of the main gene promoter (T0), and downstream of the coding regions (T1-T10) are marked by blue bars. The repeats composing the enhancer (13 according to the sequence from Genbank accession number BK000964) are shown. ETS, external transcribed spacer. (b) Description of active, inactive and silent rRNA genes based on transcription, chromatin and epigenetic state and factors regulating their state. The binding of UBF and NoRC (TIP5 and SNF2H) define active and silent rRNA genes. Inactive rRNA genes are non-transcribed repeats that lack promoter DNA methylation, are nucleosome-packed at the coding region, and are not bound by UBF or NoRC. The structure of inactive genes can be mediated by the nucleosome remodeling and deacetylase (NuRD) complex, the energy-dependent nucleolar silencing complex (eNOSC) or other yet unknown regulators.
Figure 2
Figure 2
Regulation of rRNA gene chromatin state embryonic stem cells. (a) Scheme showing the synthesis of IGS-rRNA from the mouse spacer promoter and its processing into pRNA, a reaction mediated by DHX9 [57,64]. (b) Model showing the chromatin organization of the nucleus and nucleolus of ESCs (open, euchromatic) and differentiated cells (closed, heterochromatic). In ESCs, IGS-rRNA is not processed with consequent lack of mature pRNA [48]. IGS-rRNA impairs the association of TIP5 with TTF1 and TIP5 recruitment to rRNA genes. Consequently, all rRNA genes are kept euchromatic and active in ESCs. Upon differentiation, mature pRNA is produced and promotes TIP5-TTF1 interaction that is productive for TIP5 guiding to rRNA genes and formation of heterochromatin at nucleoli. The formation of silent and heterochromatic rRNA genes coincides with the remodeling of the genome from a euchromatic into a heterochromatic state that favors the exit from pluripotency.
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