PT  - JOURNAL ARTICLE
AU  - Anton Ogorodnikov
AU  - Michal Levin
AU  - Surendra Tattikota
AU  - Sergey Tokalov
AU  - Mainul Hoque
AU  - Denise Scherzinger
AU  - Federico Marini
AU  - Ansgar Poetsch
AU  - Harald Binder
AU  - Stephan Macher-Göppinger
AU  - Bin Tian
AU  - Michael Schaefer
AU  - Karl Lackner
AU  - Frank Westermann
AU  - Sven Danckwardt
TI  - PCF11 links alternative polyadenylation to formation and spontaneous regression of neuroblastoma
AID  - 10.1101/426536
DP  - 2018 Jan 01
TA  - bioRxiv
PG  - 426536
4099  - http://biorxiv.org/content/early/2018/11/15/426536.short
4100  - http://biorxiv.org/content/early/2018/11/15/426536.full
AB  - Diversification at the transcriptome 3’end is an important and evolutionarily conserved layer of gene regulation associated with differentiation and dedifferentiation processes. However the underlying mechanisms and functional consequences are poorly defined. 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 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.