Division of Research, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia.
Nucleic Acids Res. 2011 Apr;39(8):3267-81. doi: 10.1093/nar/gkq1205. Epub 2010 Dec 21.
Loss of c-MYC is required for downregulation of ribosomal RNA (rRNA) gene (rDNA) transcription by RNA Polymerase I (Pol I) during granulocyte differentiation. Here, we demonstrate a robust reduction of Pol I loading onto rDNA that along with a depletion of the MYC target gene upstream binding factor (UBF) and a switch from epigenetically active to silent rDNA accompanies this MYC reduction. We hypothesized that MYC may coordinate these mechanisms via direct regulation of multiple components of the Pol I transcription apparatus. Using gene expression arrays we identified a 'regulon' of Pol I factors that are both downregulated during differentiation and reinduced in differentiated granulocytes upon activation of the MYC-ER transgene. This regulon includes the novel c-MYC target genes RRN3 and POLR1B. Although enforced MYC expression during granulocyte differentiation was sufficient to increase the number of active rRNA genes, its activation in terminally differentiated cells did not alter the active to inactive gene ratio despite increased rDNA transcription. Thus, c-MYC dynamically controls rDNA transcription during granulocytic differentiation through the orchestrated transcriptional regulation of core Pol I factors and epigenetic modulation of number of active rRNA genes.
在粒细胞分化过程中，c-MYC 的缺失对于 RNA 聚合酶 I（Pol I）下调核糖体 RNA（rRNA）基因（rDNA）转录是必需的。在这里，我们证明了 Pol I 对 rDNA 的加载量显著减少，同时 MYC 靶基因上游结合因子（UBF）耗竭，以及 rDNA 从表观遗传活性转变为沉默状态。我们假设 MYC 可能通过直接调节 Pol I 转录装置的多个组件来协调这些机制。使用基因表达谱芯片，我们鉴定了一个 Pol I 因子的“调控子”，在分化过程中这些因子都下调，并且在 MYC-ER 转基因激活后在分化的粒细胞中重新诱导。这个调控子包括新的 c-MYC 靶基因 RRN3 和 POLR1B。虽然在粒细胞分化过程中强制表达 MYC 足以增加活性 rRNA 基因的数量，但在终末分化细胞中其激活并不能改变活性基因与非活性基因的比例，尽管 rDNA 转录增加。因此，c-MYC 通过协调 Pol I 核心因子的转录调控和活性 rRNA 基因数量的表观遗传调节，在粒细胞分化过程中动态控制 rDNA 转录。
