Transcriptome 3′end organization by PCF11 links alternative polyadenylation to formation and neuronal differentiation of neuroblastoma

Anton Ogorodnikov, Michal Levin, Surendra Tattikota, Sergey Tokalov, Mainul Hoque, Denise Scherzinger, Federico Marini, Ansgar Poetsch, Harald Binder, Stephan Macher-Göppinger, Hans Christian Probst, Bin Tian, Michael Schaefer, Karl J. Lackner, Frank Westermann and Sven Danckwardt ()
Additional contact information
Anton Ogorodnikov: University Medical Centre Mainz
Michal Levin: University Medical Centre Mainz
Surendra Tattikota: University Medical Centre Mainz
Sergey Tokalov: University Medical Centre Mainz
Mainul Hoque: Rutgers New Jersey Medical School
Denise Scherzinger: University Medical Centre Mainz
Federico Marini: University Medical Centre Mainz
Ansgar Poetsch: Max-Planck-Institute for Heart and Lung Research
Harald Binder: Faculty of Medicine and Medical Center—University of Freiburg
Stephan Macher-Göppinger: University Medical Centre Mainz
Hans Christian Probst: University Medical Centre Mainz
Bin Tian: Rutgers New Jersey Medical School
Michael Schaefer: University Medical Centre Mainz
Karl J. Lackner: University Medical Centre Mainz
Frank Westermann: German Cancer Research Centre (DKFZ)
Sven Danckwardt: University Medical Centre Mainz

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: Abstract 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07580-5

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DOI: 10.1038/s41467-018-07580-5

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