Joshi Gaurav, Eberhardt Alexander Otto, Lange Lisa, Winkler René, Hoffmann Steve, Kosan Christian, Bierhoff Holger
Center for Molecular Biomedicine (CMB), Institute of Biochemistry and Biophysics, Friedrich Schiller University Jena, Hans-Knöll-Str. 2, 07745 Jena, Germany.
Indian Institute of Science Education and Research (IISER), Dr. Homi Bhabha Road, Pune 411008, India.
Cancers (Basel). 2020 Oct 16;12(10):3009. doi: 10.3390/cancers12103009.
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- 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 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.
细胞的一个主要转录产物是核糖体RNA（rRNA），它由RNA聚合酶I（Pol I）从多拷贝的rRNA基因（rDNA）合成。启动子CpG甲基化导致rDNA片段的组成性沉默，有助于稳定这些原本高度活跃的基因座。在由癌蛋白Myc驱动的癌症中，过量的Myc直接刺激rDNA转录。然而，尚不清楚这种机制在致癌过程中的何时出现，以及Myc驱动的rDNA激活如何影响表观遗传沉默。在这里，我们使用Eµ-小鼠模型来研究Myc驱动的B细胞淋巴瘤发生过程中的rDNA转录和表观遗传调控。我们开发了一种精细的细胞计数策略，以从肿瘤起始、促进和进展阶段分离B细胞，并发现仅在成熟淋巴瘤中18S和rRNA基因表达均大幅增加。令人惊讶的是，启动子CpG甲基化和rDNA沉默机制在肿瘤进展状态下也强烈上调。数据表明致癌性Myc在rDNA调控中具有双重作用，既促进转录又加强对沉默重复序列的抑制，这可能为干扰癌细胞中Myc功能提供一个新的角度。
