Antisense targeting of decoy exons can reduce intron retention and increase protein expression in human erythroblasts.

Antisense targeting of decoy exons can reduce intron retention and increase protein expression in human erythroblasts.
RNA. 2020 Apr 20;:
Authors: Parra MK, Zhang W, Vu J, DeWitt MA, Conboy JG
Abstract
The decoy exon model has been proposed to regulate a subset of intron retention (IR) events involving predominantly larger introns (>1kb). Splicing reporter studies have shown that decoy splice sites are essential for activity, suggesting that decoys act by engaging intron-terminal splice sites and competing with cross-intron interactions required for intron excision. The decoy model predicts that antisense oligonucleotides may be able to block decoy splice sites in endogenous pre-mRNA, thereby reducing IR and increasing productive gene expression. Indeed, we now demonstrate that targeting a decoy 5' splice site in the O-GlcNAc transferase (OGT) gene reduced IR from ~80% to ~20% in primary human erythroblasts, accompanied by increases in spliced OGT RNA and OGT protein expression. The remaining OGT IR was refractory to antisense treatment and might be mediated by independent mechanism(s). In contrast, other retained introns were strongly dependent on decoy function, since antisense targeting of decoy 5' splice sites greatly reduced (SNRNP70) or nearly eliminated (SF3B1) IR in two widely expressed splicing factors, and also greatly reduced IR in transcripts encoding the erythroid-specific structural protein, alpha-spectrin (SPTA1). T...

Source: RNA - April 19, 2020 Category: Genetics & Stem Cells Authors: Parra MK, Zhang W, Vu J, DeWitt MA, Conboy JG Tags: RNA Source Type: research