Changes in long-range rDNA-genomic interactions associate with altered RNA polymerase II gene programs during malignant transformation

Diesch, Jeannine; Bywater, Megan J.; Sanij, Elaine; Cameron, Donald P.; Schierding, William; Brajanovski, Natalie; Son, Jinbae; Sornkom, Jirawas; Hein, Nadine; Evers, M.; Pearson, Richard B.; McArthur, Grant A.; Ganley, Austen R. D.; O’Sullivan, Justin M.; Hannan, Ross D.; Poortinga, Gretchen

doi:10.1038/s42003-019-0284-y

Cited by 39 publications

(60 citation statements)

References 103 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The reduced rDNA copy number in the ZFN-targeted TOV112D cells is associated with an increased proportion of active rDNA repeats, in agreement with previous reports in yeast showing altering rDNA copy number modulated rDNA chromatin states (Ide et al, 2010). The increased proportion of active rDNA repeats may result from rDNA class switching, specifically the reduced pool of rDNA repeats promotes UBF binding to any inactive repeats thus converting them to active repeats (Diesch et al, 2019). Alternatively, ZNF deletion may selectively target inactive rDNA repeats.…”

Section: Discussionsupporting

confidence: 89%

“…Inactive rDNA repeats, which lack UBF binding, can be CpG methylated at the rDNA promoter and stably silenced, or non-methylated and hence be in a "pseudo-silent" state (Sanij et al, 2008;Sanij and Hannan, 2009;Hamperl et al, 2013). UBF binding/release is critical for the conversion between active/inactive rDNA repeats, termed rDNA class switching (Sanij et al, 2008;Hamdane et al, 2014;Diesch et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

“…et al, 2013;Valori et al, 2020). This link is underscored by the modulation of rDNA transcription and rDNA silencing during differentiation and tumorigenesis (Conconi et al, 1989;Sanij et al, 2008;Grummt and Langst, 2013;Hamperl et al, 2013;Hayashi et al, 2014;Savic et al, 2014;Woolnough et al, 2016;Diesch et al, 2019;Prakash et al, 2019). Increased rDNA transcription is a well-known hallmark of cancer.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

rDNA Chromatin Activity Status as a Biomarker of Sensitivity to the RNA Polymerase I Transcription Inhibitor CX-5461

Son

Hannan

Poortinga

et al. 2020

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

rDNA Chromatin Activity Status as a Biomarker of Sensitivity to the RNA Polymerase I Transcription Inhibitor CX-5461

Son

Hannan

Poortinga

et al. 2020

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Accordingly, elevation of Myc abundance in pre/B220 low and tumor cells may lead to ‘invasion’ of novel rDNA sites and in turn upstream promoter activation. On the other hand, general rDNA chromatin opening in Eµ- Myc lymphomas has been shown [ 52 ], indicating an epigenetic ripple effect from the main to the upstream promoter. Both mechanisms are not mutually exclusive and may even act in concert, leading to the high levels of pRNA that we have observed in primary and cultured lymphoma cells.…”

Section: Discussionmentioning

confidence: 99%

Dichotomous Impact of Myc on rRNA Gene Activation and Silencing in B Cell Lymphomagenesis

Joshi

Eberhardt

Lange

et al. 2020

Cancers

View full text Add to dashboard Cite

A major transcriptional output of cells is ribosomal RNA (rRNA), synthesized by RNA polymerase I (Pol I) from multicopy rRNA genes (rDNA). Constitutive silencing of an rDNA fraction by promoter CpG methylation contributes to the stabilization of these otherwise highly active loci. In cancers driven by the oncoprotein Myc, excessive Myc directly stimulates rDNA transcription. However, it is not clear when during carcinogenesis this mechanism emerges, and how Myc-driven rDNA activation affects epigenetic silencing. Here, we have used the Eµ-Myc mouse model to investigate rDNA transcription and epigenetic regulation in Myc-driven B cell lymphomagenesis. We have developed a refined cytometric strategy to isolate B cells from the tumor initiation, promotion, and progression phases, and found a substantial increase of both Myc and rRNA gene expression only in established lymphoma. Surprisingly, promoter CpG methylation and the machinery for rDNA silencing were also strongly up-regulated in the tumor progression state. The data indicate a dichotomous role of oncogenic Myc in rDNA regulation, boosting transcription as well as reinforcing repression of silent repeats, which may provide a novel angle on perturbing Myc function in cancer cells.

show abstract

“…Previous studies in somatic cells highlighted the nucleolus as one of the subnuclear compartments that serves for the organization of the inactive chromatin in the cell [4][5][6][7][8]. Recent data have also started to suggest that the nucleolus has an active role in the remodeling of the ESC genome, which, during differentiation, undergoes structural rearrangements and the formation of highly condensed and transcriptional repressed heterochromatic regions that cluster at the nucleolus or at the nuclear periphery [23,79,[82][83][84].…”

Section: Nucleolus and Rrna Genes In Embryonic Stem Cellsmentioning

confidence: 99%

Nucleolus and rRNA Gene Chromatin in Early Embryo Development

Kresoja‐Rakic

Santoro

2019

Trends in Genetics

View full text Add to dashboard Cite

The nucleolus is the largest substructure in the nucleus and forms around the nucleolar organizer regions (NORs), which comprise hundreds of rRNA genes. Recent evidence highlights further functions of the nucleolus that go beyond ribosome biogenesis. Data indicate that the nucleolus acts 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 discuss recent findings that have revealed how nucleolar structure and rRNA gene chromatin states are regulated during early mammalian development and their contribution to the higher-order spatial organization of the genome. The Multifunctional Nucleolus: From Ribosome Producer to Organizer of Genome Architecture The nucleolus (see Glossary) is the largest subnuclear compartment of the cell and forms around regions of chromosomes containing stretches of tandem repetitive rRNA genes, known as nucleolar organizer regions (NORs). The nucleolus is responsible for the production of ribosomes, a highly regulated process that is essential for growth and development. Ribosome biogenesis is initiated in the nucleolus by RNA polymerase I (Pol I), which, together with a dedicated set of basal transcription factors, such as TIF1A, the TBP-TAFI complex SL1, and the DNA architectural upstream binding factor (UBF) [1,2], transcribes hundreds of rRNA genes to generate 45S/47S pre-rRNA in mammalian cells (Figure 1A). This rRNA precursor is chemically modified and processed to form 28S, 18S, and 5.8S rRNAs, which are then assembled with ribosomal proteins and 5S rRNA and exported from the nucleus to give rise to active ribosomes in the cytoplasm [3]. Increasing evidence suggests that the function of the nucleolus and rRNA genes goes beyond ribosome biogenesis. One aspect that has received significant interest over the past decade is the link between the nucleolus and rRNA genes with the organization of genome architecture. Clustering of heterochromatin at nucleoli is a phenomenon that occurs in all cells. Furthermore, regions located close to the nucleolus (nucleolar-associated domains, NADs) have low gene densities, low transcriptional levels, and repressive histone modifications [4-8]. Since similar heterochromatic and repressive regions are also located to the nuclear lamina, the nucleolus, together with the nuclear lamina, can be considered the hub for the organization of the inactive chromatin in the cell [8-10]. In this review, we address the role of the nucleolus as a subnuclear compartment for the organization of heterochromatin. We discuss recent findings that have revealed how nucleolar structure and rRNA gene chromatin states are regulated during gametogenesis and early mammalian development, and their contribution in the higher-order spatial organization of the genome. Nucleolus and rRNA Genes in Somatic Cells In somatic cells, the nucleolus is a membraneless compartment with a peculiar tripartite architecture: the fibrillar cen...

show abstract

Changes in long-range rDNA-genomic interactions associate with altered RNA polymerase II gene programs during malignant transformation

Cited by 39 publications

References 103 publications

rDNA Chromatin Activity Status as a Biomarker of Sensitivity to the RNA Polymerase I Transcription Inhibitor CX-5461

rDNA Chromatin Activity Status as a Biomarker of Sensitivity to the RNA Polymerase I Transcription Inhibitor CX-5461

Dichotomous Impact of Myc on rRNA Gene Activation and Silencing in B Cell Lymphomagenesis

Nucleolus and rRNA Gene Chromatin in Early Embryo Development

Contact Info

Product

Resources

About