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NMD is required for timely cell fate transitions by fine-tuning gene expression and controlling translation

Elena Galimberti, Robert Sehlke, Michelle Huth, Marius Garmhausen, Merrit Romeike, Julia Ramesmayer, Sarah Stummer, Fabian Titz-Teixeira, Veronika Herzog, Anastasia Chugunova, Katrin Friederike Leesch, Laurenz Holcik, Klara Weipoltshammer, Laura Santini, Andreas Lackner, Arndt von Haeseler, Christa Bücker, Andrea Pauli, Christian Schoefer, Stefan L. Ameres, Austin Smith, Andreas Beyer, Martin Leeb
doi: https://doi.org/10.1101/2020.07.07.180133
Elena Galimberti
1Max Perutz Labs Vienna, University of Vienna, Vienna BioCenter, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria
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Robert Sehlke
2CECAD Cologne, Joseph-Stelzmann-Str. 26 50931 Köln, Germany
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Michelle Huth
1Max Perutz Labs Vienna, University of Vienna, Vienna BioCenter, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria
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Marius Garmhausen
2CECAD Cologne, Joseph-Stelzmann-Str. 26 50931 Köln, Germany
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Merrit Romeike
1Max Perutz Labs Vienna, University of Vienna, Vienna BioCenter, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria
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Julia Ramesmayer
1Max Perutz Labs Vienna, University of Vienna, Vienna BioCenter, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria
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Sarah Stummer
1Max Perutz Labs Vienna, University of Vienna, Vienna BioCenter, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria
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Fabian Titz-Teixeira
2CECAD Cologne, Joseph-Stelzmann-Str. 26 50931 Köln, Germany
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Veronika Herzog
3Institute of Molecular Biotechnology, Vienna BioCenter, Dr.-Bohr-Gasse 3, 1030 Vienna, Austria
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Anastasia Chugunova
4Research Institute of Molecular Pathology, Vienna BioCenter, Campus-Vienna-Biocenter 1, 1030 Vienna, Austria
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Katrin Friederike Leesch
4Research Institute of Molecular Pathology, Vienna BioCenter, Campus-Vienna-Biocenter 1, 1030 Vienna, Austria
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Laurenz Holcik
1Max Perutz Labs Vienna, University of Vienna, Vienna BioCenter, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria
6Center for Integrative Bioinformatics Vienna, Max Perutz Labs, University of Vienna and Medical University of Vienna, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria
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Klara Weipoltshammer
5Department for Cell and Developmental Biology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, Austria
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Laura Santini
1Max Perutz Labs Vienna, University of Vienna, Vienna BioCenter, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria
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Andreas Lackner
1Max Perutz Labs Vienna, University of Vienna, Vienna BioCenter, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria
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Arndt von Haeseler
1Max Perutz Labs Vienna, University of Vienna, Vienna BioCenter, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria
6Center for Integrative Bioinformatics Vienna, Max Perutz Labs, University of Vienna and Medical University of Vienna, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria
7Bioinformatics and Computational Biology, Faculty of Computer Science, University of Vienna, Vienna, Austria
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Christa Bücker
1Max Perutz Labs Vienna, University of Vienna, Vienna BioCenter, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria
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Andrea Pauli
4Research Institute of Molecular Pathology, Vienna BioCenter, Campus-Vienna-Biocenter 1, 1030 Vienna, Austria
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Christian Schoefer
5Department for Cell and Developmental Biology, Medical University of Vienna, Schwarzspanierstrasse 17, 1090 Vienna, Austria
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Stefan L. Ameres
3Institute of Molecular Biotechnology, Vienna BioCenter, Dr.-Bohr-Gasse 3, 1030 Vienna, Austria
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Austin Smith
8Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK
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Andreas Beyer
2CECAD Cologne, Joseph-Stelzmann-Str. 26 50931 Köln, Germany
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Martin Leeb
1Max Perutz Labs Vienna, University of Vienna, Vienna BioCenter, Dr.-Bohr-Gasse 9, 1030 Vienna, Austria
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  • For correspondence: martin.leeb@univie.ac.at
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ABSTRACT

Cell fate transitions depend on balanced rewiring of transcription and translation programmes to mediate ordered developmental progression. Components of the nonsense-mediated mRNA decay (NMD) pathway have been implicated in regulating embryonic stem cell (ESC) differentiation, but the exact mechanism is unclear. Here we show that NMD controls the translation initiation factor Eif4a2 and its premature termination codon encoding isoform (Eif4a2PTC). NMD deficiency leads to translation of a specific truncated Eif4a2 protein, which elicits increased translation rates and causes significant delays in mouse ESC differentiation. Thereby a previously unknown feedback loop between NMD and translation initiation is established. Our results illustrate a clear hierarchy between KOs in severity of target deregulation and differentiation phenotype (Smg5 > Smg6 > Smg7), which highlights heterodimer-independent functions for Smg5 and Smg7. Together, our findings expose an intricate link between mRNA stability and translation initiation control that must be maintained for normal dynamics of cell state transitions.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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NMD is required for timely cell fate transitions by fine-tuning gene expression and controlling translation
Elena Galimberti, Robert Sehlke, Michelle Huth, Marius Garmhausen, Merrit Romeike, Julia Ramesmayer, Sarah Stummer, Fabian Titz-Teixeira, Veronika Herzog, Anastasia Chugunova, Katrin Friederike Leesch, Laurenz Holcik, Klara Weipoltshammer, Laura Santini, Andreas Lackner, Arndt von Haeseler, Christa Bücker, Andrea Pauli, Christian Schoefer, Stefan L. Ameres, Austin Smith, Andreas Beyer, Martin Leeb
bioRxiv 2020.07.07.180133; doi: https://doi.org/10.1101/2020.07.07.180133
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NMD is required for timely cell fate transitions by fine-tuning gene expression and controlling translation
Elena Galimberti, Robert Sehlke, Michelle Huth, Marius Garmhausen, Merrit Romeike, Julia Ramesmayer, Sarah Stummer, Fabian Titz-Teixeira, Veronika Herzog, Anastasia Chugunova, Katrin Friederike Leesch, Laurenz Holcik, Klara Weipoltshammer, Laura Santini, Andreas Lackner, Arndt von Haeseler, Christa Bücker, Andrea Pauli, Christian Schoefer, Stefan L. Ameres, Austin Smith, Andreas Beyer, Martin Leeb
bioRxiv 2020.07.07.180133; doi: https://doi.org/10.1101/2020.07.07.180133

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