RT Journal Article
SR Electronic
T1 Diminished miRNA activity is associated with aberrant cytoplasmic intron retention in ALS pathogenesis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.01.27.428555
DO 10.1101/2021.01.27.428555
A1 Marija Petric-Howe
A1 Hamish Crerar
A1 Jacob Neeves
A1 Giulia E. Tyzack
A1 Rickie Patani
A1 Raphaëlle Luisier
YR 2021
UL http://biorxiv.org/content/early/2021/01/28/2021.01.27.428555.abstract
AB 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 genes 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.Competing Interest StatementThe authors have declared no competing interest.