Uncovering the dynamics and consequences of RNA isoform changes during neuronal 
differentiation

Ulicevic, Jelena; Shao, Zhihao; Jasnovidova, Olga; Bressin, Annkatrin; Gajos, Martyna; Ng, Alex Hm; Annaldasula, Siddharth; Meierhofer, David; Church, George M.; Busskamp, Volker; Mayer, Andreas

doi:10.1038/s44320-024-00039-4

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Uncovering the dynamics and consequences of RNA isoform changes during neuronal differentiation

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Ulicevic, Jelena
High-Resolution Functional Genomics (Andreas Mayer), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Shao, Zhihao
High-Resolution Functional Genomics (Andreas Mayer), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;
Evolutionary Genomics (Peter Arndt), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Jasnovidova, Olga
High-Resolution Functional Genomics (Andreas Mayer), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Bressin, Annkatrin
High-Resolution Functional Genomics (Andreas Mayer), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Gajos, Martyna
High-Resolution Functional Genomics (Andreas Mayer), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Meierhofer, David
Mass Spectrometry Facility, Scientific Service, Max Planck Institute for Molecular Genetics, Max Planck Society;

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Mayer, Andreas
High-Resolution Functional Genomics (Andreas Mayer), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Ulicevic, J., Shao, Z., Jasnovidova, O., Bressin, A., Gajos, M., Ng, A. H., et al. (2024). Uncovering the dynamics and consequences of RNA isoform changes during neuronal differentiation. Molecular Systems Biology. doi:10.1038/s44320-024-00039-4.

Cite as: https://hdl.handle.net/21.11116/0000-000F-5BC7-B

Abstract

Static gene expression programs have been extensively characterized in stem cells and mature human cells. However, the dynamics of RNA isoform changes upon cell-state-transitions during cell differentiation, the determinants and functional consequences have largely remained unclear. Here, we established an improved model for human neurogenesis in vitro that is amenable for systems-wide analyses of gene expression. Our multi-omics analysis reveals that the pronounced alterations in cell morphology correlate strongly with widespread changes in RNA isoform expression. Our approach identifies thousands of new RNA isoforms that are expressed at distinct differentiation stages. RNA isoforms mainly arise from exon skipping and the alternative usage of transcription start and polyadenylation sites during human neurogenesis. The transcript isoform changes can remodel the identity and functions of protein isoforms. Finally, our study identifies a set of RNA binding proteins as a potential determinant of differentiation stage-specific global isoform changes. This work supports the view of regulated isoform changes that underlie state-transitions during neurogenesis.