Physiological intron retaining transcripts in the cytoplasm abound during human motor neurogenesis
- Marija Petrić Howe1,2,6,
- Hamish Crerar1,2,6,
- Jacob Neeves1,2,
- Jasmine Harley1,2,
- Giulia E. Tyzack1,2,
- Pierre Klein1,3,
- Andres Ramos3,
- Rickie Patani1,2,7 and
- Raphaëlle Luisier4,5,7
- 1The Francis Crick Institute, London NW1 1AT, United Kingdom;
- 2Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3AR, United Kingdom;
- 3Research Department of Structural and Molecular Biology, University College London, London WC1E 6XA, United Kingdom;
- 4Idiap Research Institute, Genomics and Health Informatics, CH-1920 Martigny, Switzerland;
- 5SIB Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland
Abstract
Intron retention (IR) is now recognized as a dominant splicing event during motor neuron (MN) development; however, the role and regulation of intron-retaining transcripts (IRTs) localized to the cytoplasm remain particularly understudied. Here we show that IR is a physiological process that is spatiotemporally regulated during MN lineage restriction and that IRTs in the cytoplasm are detected in as many as 13% (n = 2297) of the genes expressed during this process. We identify a major class of cytoplasmic IRTs that are not associated with reduced expression of their own genes but instead show a high capacity for RNA-binding protein and miRNA occupancy. Finally, we show that ALS-causing VCP mutations lead to a selective increase in cytoplasmic abundance of this particular class of IRTs, which in turn temporally coincides with an increase in the nuclear expression level of predicted miRNA target genes. Altogether, our study identifies a previously unrecognized class of cytoplasmic intronic sequences with potential regulatory function beyond gene expression.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.276898.122.
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Freely available online through the Genome Research Open Access option.
- Received May 3, 2022.
- Accepted September 16, 2022.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
