Diminished miRNA activity is associated with aberrant cytoplasmic intron retention in ALS pathogenesis [article]

Marija Petric-Howe, Hamish Crerar, Jacob Neeves, Giulia E Tyzack, Rickie Patani, Raphaelle Luisier
2021 bioRxiv   pre-print
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. By resolving the spatiotemporal dynamics of IR underlying distinct stages of MN lineage restriction, we identify a cytoplasmic group of IRTs that is not associated with reduced expression of their own genes but instead with an upregulation of predicted target
more » ... enes of specific miRNAs, the motifs of which are enriched within the intronic sequences of this group. Next, we show that ALS-causing VCP mutations lead to a selective increase in IR of this particular class of introns. This in turn temporally coincides with an increase in the expression level of predicted target genes of these miRNAs, providing a potential mechanistic insight into ALS pathogenesis. Altogether, we propose a novel role for the cytoplasmic intronic sequences in regulating miRNA activity through miRNA sequestration, which potentially contributes to ALS pathogenesis.
doi:10.1101/2021.01.27.428555 fatcat:pls3zplavbbbjlnymip6empyoa