Nuclear compartmentalization of TERT mRNA and TUG1 lncRNA is driven by intron retention

Gabrijela Dumbović (), Ulrich Braunschweig, Heera K. Langner, Michael Smallegan, Josep Biayna, Evan P. Hass, Katarzyna Jastrzebska, Benjamin Blencowe, Thomas R. Cech, Marvin H. Caruthers and John L. Rinn ()
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Gabrijela Dumbović: University of Colorado Boulder
Ulrich Braunschweig: University of Toronto
Heera K. Langner: University of Colorado Boulder
Michael Smallegan: BioFrontiers Institute, University of Colorado Boulder
Josep Biayna: Institute for Research in Biomedicine, Parc Científic de Barcelona
Evan P. Hass: University of Colorado Boulder
Katarzyna Jastrzebska: University of Colorado Boulder
Benjamin Blencowe: University of Toronto
Thomas R. Cech: University of Colorado Boulder
Marvin H. Caruthers: University of Colorado Boulder
John L. Rinn: University of Colorado Boulder

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract The spatial partitioning of the transcriptome in the cell is an important form of gene-expression regulation. Here, we address how intron retention influences the spatio-temporal dynamics of transcripts from two clinically relevant genes: TERT (Telomerase Reverse Transcriptase) pre-mRNA and TUG1 (Taurine-Upregulated Gene 1) lncRNA. Single molecule RNA FISH reveals that nuclear TERT transcripts uniformly and robustly retain specific introns. Our data suggest that the splicing of TERT retained introns occurs during mitosis. In contrast, TUG1 has a bimodal distribution of fully spliced cytoplasmic and intron-retained nuclear transcripts. We further test the functionality of intron-retention events using RNA-targeting thiomorpholino antisense oligonucleotides to block intron excision. We show that intron retention is the driving force for the nuclear compartmentalization of these RNAs. For both RNAs, altering this splicing-driven subcellular distribution has significant effects on cell viability. Together, these findings show that stable retention of specific introns can orchestrate spatial compartmentalization of these RNAs within the cell. This process reveals that modulating RNA localization via targeted intron retention can be utilized for RNA-based therapies.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23221-w

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DOI: 10.1038/s41467-021-23221-w

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