The Role of rDNA Clusters in Global Epigenetic Gene Regulation

Abstract

The regulation of gene expression has been studied for decades, but the underlying mechanisms are still not fully understood. As well as local and distant regulation, there are specific mechanisms of regulation during development and physiological modulation of gene activity in differentiated cells. Current research strongly supports a role for the 3D chromosomal structure in the regulation of gene expression. However, it is not known whether the genome structure reflects the formation of active or repressed chromosomal domains or if these structures play a primary role in the regulation of gene expression. During early development, heterochromatinization of ribosomal DNA (rDNA) is coupled with silencing or activation of the expression of different sets of genes. Although the mechanisms behind this type of regulation are not known, rDNA clusters shape frequent inter-chromosomal contacts with a large group of genes controlling development. This review aims to shed light on the involvement of clusters of ribosomal genes in the global regulation of gene expression. We also discuss the possible role of RNA-mediated and phase-separation mechanisms in the global regulation of gene expression by nucleoli.

Induction of the Erythroid Differentiation of K562 Cells Is Coupled with Changes in the Inter-Chromosomal Contacts of rDNA Clusters

“…However, it has been observed that rDNA contact sites can exactly correspond to repressed chromatin areas [ 14 ] and that rDNA contacts are enriched in segments of closed, repressed, late-replicating chromatin, CTCF-binding sites, and with the regions possessing the most frequent DNA DSBs inside active and silenced genes [ 15 , 16 ]. Taken together, these facts support the view on the role of rDNA genes in the global epigenetic regulation of gene expression by the shaping of physiological 3D chromosomal structures [ 17 , 18 ]. However, to date, it has not been demonstrated if rDNA contacts are changed during differentiation and if these changes are associated with alterations in the expression of developmental genes.…”

“…Upon the differentiation of K562 cells, many regions preserved their inter-chromosomal contacts with rDNA genes. It was observed that rDNA contacts located inside DUX4 genes were characteristic of different human cell lines and were very sensitive to heat-shock treatment, mostly disappearing following a brief treatment [ 17 , 28 ]. This was why we were interested in verifying whether the initial differentiation step of K562 cells affected the contacts of rDNA clusters with DUX4 genes.…”

Local G-quadruplexes are not a major determinant of altered gene expression in BLM-deficient cells

“…Recent studies of 3D chromatin organization indicate that the rDNA locus can play an important role in global regulation of gene expression during development, e.g. through contacts to H3K27ac-marked super-enhancers (reviewed by (25)). In support of this hypothesis, we observed H3K27ac regions as the second most strongly affected genomic feature, having a 5% increase in nucleosome density in the absence of BLM.…”

Genes Possessing the Most Frequent DNA DSBs Are Highly Associated with Development and Cancers, and Essentially Overlap with the rDNA-Contacting Genes

“…Among these genes are active and silent genes (Figure 4). rDNA contacts can be involved in dynamic regulatory contacts with the genes involved in development and cancers via the formation of phase-separated condensates [33]. It is also possible that, as far as nucleoli possess different factors capable of DNA repair, these contacts are a part of the DNA damage response [33].…”