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Post-transcriptional remodelling is temporally deregulated during motor neurogenesis in human ALS models

Raphaelle Luisier, Giulia E. Tyzack, Claire E. Hall, Jernej Ule, Nicholas M. Luscombe, Rickie Patani
doi: https://doi.org/10.1101/180372
Raphaelle Luisier
1The Francis Crick Institute, 1 Midland Road, London NW1 1AT,
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Giulia E. Tyzack
2Department of Molecular Neuroscience UCL Institute of Neurology, Queen Square, London, UK
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Claire E. Hall
2Department of Molecular Neuroscience UCL Institute of Neurology, Queen Square, London, UK
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Jernej Ule
1The Francis Crick Institute, 1 Midland Road, London NW1 1AT,
2Department of Molecular Neuroscience UCL Institute of Neurology, Queen Square, London, UK
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Nicholas M. Luscombe
1The Francis Crick Institute, 1 Midland Road, London NW1 1AT,
3UCL Genetics Institute, University College London, Gower Street, London WC1E 6BT, UK
4Okinawa Institute of Science & Technology Graduate University, Okinawa 904-0495, Japan
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  • For correspondence: nicholas.luscombe@crick.ac.uk rickie.patani@ucl.ac.uk
Rickie Patani
1The Francis Crick Institute, 1 Midland Road, London NW1 1AT,
2Department of Molecular Neuroscience UCL Institute of Neurology, Queen Square, London, UK
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  • For correspondence: nicholas.luscombe@crick.ac.uk rickie.patani@ucl.ac.uk
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SUMMARY

Mutations causing amyotrophic lateral sclerosis (ALS) strongly implicate regulators of RNA-processing that are ubiquitously expressed throughout development. To understand the molecular impact of ALS-causing mutations on early neuronal development and disease, we performed transcriptomic analysis of differentiated human control and VCP-mutant induced pluripotent stem cells (iPSCs) during motor neurogenesis. We identify intron retention (IR) as the predominant splicing change affecting early stages of wild-type neural differentiation, targeting key genes involved in the splicing machinery. Importantly, IR occurs prematurely in VCP-mutant cultures compared with control counterparts; these events are also observed in independent RNAseq datasets from SOD1- and FUS-mutant motor neurons (MNs). Together with related effects on 3’UTR length variation, these findings implicate alternative RNA-processing in regulating distinct stages of lineage restriction from iPSCs to MNs, and reveal a temporal deregulation of such processing by ALS mutations. Thus, ALS-causing mutations perturb the same post-transcriptional mechanisms that underlie human motor neurogenesis.

HIGHLIGHTS

  • Intron retention is the main mode of alternative splicing in early differentiation.

  • The ALS-causing VCP mutation leads to premature intron retention.

  • Increased intron retention is seen with multiple ALS-causing mutations.

  • Transcriptional programs are unperturbed despite post-transcriptional defects.

eTOC BLURB Luisier et al. identify post-transcriptional changes underlying human motor neurogenesis: extensive variation in 3’ UTR length and intron retention (IR) are the early predominant modes of splicing. The VCP mutation causes IR to occur prematurely during motor neurogenesis and these events are validated in other ALS-causing mutations, SOD1 and FUS.

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 4.0 International license.
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Posted August 24, 2017.
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Post-transcriptional remodelling is temporally deregulated during motor neurogenesis in human ALS models
Raphaelle Luisier, Giulia E. Tyzack, Claire E. Hall, Jernej Ule, Nicholas M. Luscombe, Rickie Patani
bioRxiv 180372; doi: https://doi.org/10.1101/180372
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Post-transcriptional remodelling is temporally deregulated during motor neurogenesis in human ALS models
Raphaelle Luisier, Giulia E. Tyzack, Claire E. Hall, Jernej Ule, Nicholas M. Luscombe, Rickie Patani
bioRxiv 180372; doi: https://doi.org/10.1101/180372

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