Posttranscriptional Gene Regulation, Cancer Research and Experimental Haemostasis, University Medical Centre Mainz, Mainz, 55131, Germany.
Institute for Clinical Chemistry and Laboratory Medicine, University Medical Centre Mainz, Mainz, 55131, Germany.
Nat Commun. 2018 Dec 14;9(1):5331. doi: 10.1038/s41467-018-07580-5.
Diversification at the transcriptome 3'end is an important and evolutionarily conserved layer of gene regulation associated with differentiation and dedifferentiation processes. Here, we identify extensive transcriptome 3'end-alterations in neuroblastoma, a tumour entity with a paucity of recurrent somatic mutations and an unusually high frequency of spontaneous regression. Utilising extensive RNAi-screening we reveal the landscape and drivers of transcriptome 3'end-diversification, discovering PCF11 as critical regulator, directing alternative polyadenylation (APA) of hundreds of transcripts including a differentiation RNA-operon. PCF11 shapes inputs converging on WNT-signalling, and governs cell cycle, proliferation, apoptosis and neurodifferentiation. Postnatal PCF11 down-regulation induces a neurodifferentiation program, and low-level PCF11 in neuroblastoma associates with favourable outcome and spontaneous tumour regression. Our findings document a critical role for APA in tumorigenesis and describe a novel mechanism for cell fate reprogramming in neuroblastoma with potentially important clinical implications. We provide an interactive data repository of transcriptome-wide APA covering > 170 RNAis, and an APA-network map with regulatory hubs.
转录组 3'端的多样化是与分化和去分化过程相关的重要且进化上保守的基因调控层。在这里，我们在神经母细胞瘤中发现了广泛的转录组 3'端改变，神经母细胞瘤是一种实体瘤，其体细胞突变很少，自发消退的频率异常高。利用广泛的 RNAi 筛选，我们揭示了转录组 3'端多样化的景观和驱动因素，发现 PCF11 是关键的调节因子，指导包括分化 RNA 操纵子在内的数百个转录本的可变多聚腺苷酸化 (APA)。PCF11 塑造了汇聚到 WNT 信号的输入，并控制细胞周期、增殖、凋亡和神经分化。出生后 PCF11 的下调诱导神经分化程序，神经母细胞瘤中低水平的 PCF11 与有利的结果和自发肿瘤消退相关。我们的研究结果证明了 APA 在肿瘤发生中的关键作用，并描述了神经母细胞瘤中细胞命运重编程的新机制，具有潜在的重要临床意义。我们提供了一个涵盖超过 170 个 RNAi 的转录组范围 APA 的交互式数据存储库，以及一个具有调节枢纽的 APA 网络图谱。
