Abstract
Diversification at the transcriptome 3’end through alternative polyadenylation (APA) 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 general paucity of recurrent somatic mutations and an unusually high frequency of spontaneous regression. In an extensive RNAi-screening we reveal the landscape and drivers of transcriptome-3’end-diversification. We discover PCF11 as critical regulator of transcriptome-3’end-diversification, directing 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 is associated with favourable outcome and spontaneous tumour regression. Our findings document a critical role for APA in tumourigenesis and describe a novel mechanism for cell fate reprogramming in neuroblastoma with important clinical implications. An interactive data repository of transcriptome-wide APA covering >170 RNAis, and an APA-network map with regulatory hubs, is provided.
