RT Journal Article
SR Electronic
T1 PCF11 links alternative polyadenylation to formation and spontaneous regression of neuroblastoma
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 426536
DO 10.1101/426536
A1 Anton Ogorodnikov
A1 Michal Levin
A1 Surendra Tattikota
A1 Sergey Tokalov
A1 Mainul Hoque
A1 Denise Scherzinger
A1 Federico Marini
A1 Ansgar Poetsch
A1 Harald Binder
A1 Stephan Macher-Göppinger
A1 Bin Tian
A1 Michael Schaefer
A1 Karl Lackner
A1 Frank Westermann
A1 Sven Danckwardt
YR 2018
UL http://biorxiv.org/content/early/2018/11/15/426536.abstract
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.