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

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...

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Bibliographic Details
Published in:Cancers 2020-10, Vol.12 (10), p.3009
Main Authors: Joshi, Gaurav, Eberhardt, Alexander Otto, Lange, Lisa, Winkler, René, Hoffmann, Steve, Kosan, Christian, Bierhoff, Holger
Format: Article
Language:English
Subjects:
B cells
B-cell lymphoma
Biosynthesis
Cancer
Carcinogenesis
Cell activation
Cell growth
Communication
CpG islands
Development and progression
DNA methylation
DNA-directed RNA polymerase
Epigenetics
Gene expression
Gene regulation
Gene silencing
Genetic aspects
Genetic transformation
Health aspects
Lymphocytes B
Lymphoma
Lymphomas
Myc protein
RNA
RNA polymerase
rRNA
Transgenic mice
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Summary: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.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers12103009