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PCF11 connects alternative polyadenylation to formation and spontaneous regression of neuroblastoma

Anton Ogorodnikov, Michal Levin, Surendra Tattikota, Sergey Tokalov, Mainul Hoque, Denise Scherzinger, Federico Marini, Ansgar Poetsch, Harald Binder, Stephan Macher-Göppinger, Bin Tian, Michael Schaefer, Karl Lackner, Frank Westermann, Sven Danckwardt
doi: https://doi.org/10.1101/426536
Anton Ogorodnikov
1Posttranscriptional Gene Regulation, Cancer Research and Experimental Haemostasis, University Medical Centre Mainz, Germany
2Institute for Clinical Chemistry and Laboratory Medicine, University Medical Centre Mainz, Germany
3Centre for Thrombosis and Haemostasis (CTH), University Medical Centre Mainz, Germany
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Michal Levin
1Posttranscriptional Gene Regulation, Cancer Research and Experimental Haemostasis, University Medical Centre Mainz, Germany
2Institute for Clinical Chemistry and Laboratory Medicine, University Medical Centre Mainz, Germany
3Centre for Thrombosis and Haemostasis (CTH), University Medical Centre Mainz, Germany
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Surendra Tattikota
1Posttranscriptional Gene Regulation, Cancer Research and Experimental Haemostasis, University Medical Centre Mainz, Germany
2Institute for Clinical Chemistry and Laboratory Medicine, University Medical Centre Mainz, Germany
3Centre for Thrombosis and Haemostasis (CTH), University Medical Centre Mainz, Germany
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Sergey Tokalov
1Posttranscriptional Gene Regulation, Cancer Research and Experimental Haemostasis, University Medical Centre Mainz, Germany
2Institute for Clinical Chemistry and Laboratory Medicine, University Medical Centre Mainz, Germany
3Centre for Thrombosis and Haemostasis (CTH), University Medical Centre Mainz, Germany
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Mainul Hoque
4Rutgers New Jersey Medical School, USA
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Denise Scherzinger
5Institute for Biostatistics and Bioinformatics, University Medical Centre Mainz, Germany
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Federico Marini
3Centre for Thrombosis and Haemostasis (CTH), University Medical Centre Mainz, Germany
5Institute for Biostatistics and Bioinformatics, University Medical Centre Mainz, Germany
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Ansgar Poetsch
6Max-Planck-Institute for Heart and Lung Research, Germany
7Institute for Plant Biochemistry, Ruhr-University Bochum, Germany
8Plymouth University, School of Biomedical & Healthcare Sciences, Drake Circus, Plymouth PL4 8AA
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Harald Binder
3Centre for Thrombosis and Haemostasis (CTH), University Medical Centre Mainz, Germany
5Institute for Biostatistics and Bioinformatics, University Medical Centre Mainz, Germany
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Stephan Macher-Göppinger
9Institute for Pathology, University Medical Centre Mainz, Germany
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Bin Tian
4Rutgers New Jersey Medical School, USA
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Michael Schaefer
10Department of Anaesthesiology and Research Centre Translational Neurosciences, University Medical Centre Mainz, Germany
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Karl Lackner
2Institute for Clinical Chemistry and Laboratory Medicine, University Medical Centre Mainz, Germany
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Frank Westermann
11Division of Neuroblastoma Genomics, German Cancer Research Centre (DKFZ), Germany
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Sven Danckwardt
1Posttranscriptional Gene Regulation, Cancer Research and Experimental Haemostasis, University Medical Centre Mainz, Germany
2Institute for Clinical Chemistry and Laboratory Medicine, University Medical Centre Mainz, Germany
3Centre for Thrombosis and Haemostasis (CTH), University Medical Centre Mainz, Germany
12German Centre for Cardiovascular Research (DZHK), Germany
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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.

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Posted October 18, 2018.
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PCF11 connects alternative polyadenylation to formation and spontaneous regression of neuroblastoma
Anton Ogorodnikov, Michal Levin, Surendra Tattikota, Sergey Tokalov, Mainul Hoque, Denise Scherzinger, Federico Marini, Ansgar Poetsch, Harald Binder, Stephan Macher-Göppinger, Bin Tian, Michael Schaefer, Karl Lackner, Frank Westermann, Sven Danckwardt
bioRxiv 426536; doi: https://doi.org/10.1101/426536
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PCF11 connects alternative polyadenylation to formation and spontaneous regression of neuroblastoma
Anton Ogorodnikov, Michal Levin, Surendra Tattikota, Sergey Tokalov, Mainul Hoque, Denise Scherzinger, Federico Marini, Ansgar Poetsch, Harald Binder, Stephan Macher-Göppinger, Bin Tian, Michael Schaefer, Karl Lackner, Frank Westermann, Sven Danckwardt
bioRxiv 426536; doi: https://doi.org/10.1101/426536

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