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

1
Center for Molecular Biomedicine (CMB), Institute of Biochemistry and Biophysics, Friedrich Schiller University Jena, Hans-Knöll-Str. 2, 07745 Jena, Germany
2
Indian Institute of Science Education and Research (IISER), Dr. Homi Bhabha Road, Pune 411008, India
3
Leibniz-Institute on Aging—Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, 07745 Jena, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Current address: Institute of Molecular Biology (IMB), Ackermannweg 4, 55128 Mainz, Germany.
Cancers 2020, 12(10), 3009; https://doi.org/10.3390/cancers12103009
Received: 29 September 2020 / Accepted: 14 October 2020 / Published: 16 October 2020
(This article belongs to the Special Issue B Cell Lymphoma)
B cell lymphomas mostly arise from malignant transformation of mature B cells and are typically driven by elevated levels of the oncoprotein Myc. Myc is a transcription factor regulating many protein-coding genes as well as the multicopy genes encoding ribosomal RNA (rRNA). The aim of this study was to understand, how Myc impacts rRNA genes in the course of B cell lymphomagenesis. Using a transgenic mouse model, we found that Myc and rRNA gene expression strongly increase upon tumor formation. Surprisingly, Myc also facilitates epigenetic silencing of a fraction of rRNA genes, thereby safeguarding genomic integrity in lymphoma cells. Together, the results show that Myc balances high activity and stability of rRNA genes. Perturbation of this equilibrium may be used as a therapeutic strategy.
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. View Full-Text
Keywords: cancer; lymphomagenesis; Myc; ribosomal RNA; gene transcription; epigenetic regulation; CpG methylation; genomic instability cancer; lymphomagenesis; Myc; ribosomal RNA; gene transcription; epigenetic regulation; CpG methylation; genomic instability
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MDPI and ACS Style

Joshi, G.; Eberhardt, A.O.; Lange, L.; Winkler, R.; Hoffmann, S.; Kosan, C.; Bierhoff, H. Dichotomous Impact of Myc on rRNA Gene Activation and Silencing in B Cell Lymphomagenesis. Cancers 2020, 12, 3009. https://doi.org/10.3390/cancers12103009

AMA Style

Joshi G, Eberhardt AO, Lange L, Winkler R, Hoffmann S, Kosan C, Bierhoff H. Dichotomous Impact of Myc on rRNA Gene Activation and Silencing in B Cell Lymphomagenesis. Cancers. 2020; 12(10):3009. https://doi.org/10.3390/cancers12103009

Chicago/Turabian Style

Joshi, Gaurav; Eberhardt, Alexander O.; Lange, Lisa; Winkler, René; Hoffmann, Steve; Kosan, Christian; Bierhoff, Holger. 2020. "Dichotomous Impact of Myc on rRNA Gene Activation and Silencing in B Cell Lymphomagenesis" Cancers 12, no. 10: 3009. https://doi.org/10.3390/cancers12103009

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