Poison exons: tuning RNA splicing for targeted gene regulation

Poison exons (PEs) are a class of alternatively spliced exons whose inclusion targets mRNA transcripts for degradation via the nonsense-mediated decay (NMD) pathway. Although a role for NMD as an essential mRNA quality control pathway has long been appreciated, recent advances in RNA sequencing (RNA-seq) strategies and analyses have revealed that its coupling to RNA splicing is broadly used to regulate mRNA stability and abundance. Regulation of PE splicing affects patterns of targeted degradation across the transcriptome and influences gene expression in both healthy and disease states. Importantly, PEs represent a novel therapeutic opportunity to modulate the expression of disease-relevant genes with sequence-specific resolution. We review the emergence of PE splicing in endogenous gene regulation, its misregulation in disease, and the ways in which it can be leveraged for therapeutic benefit.