BioProject

Alternative splicing (AS) coupled to nonsense-mediated decay (AS-NMD) is a conserved mechanism for post-transcriptional regulation of gene expression. More...

Alternative splicing (AS) coupled to nonsense-mediated decay (AS-NMD) is a conserved mechanism for post-transcriptional regulation of gene expression. Here we show that during Dietary restriction (DR), which positively impacts health and longevity across species, AS events are significantly enhanced in Caenorhabditis elegans and mice. In C. elegans, genes involved in metabolism, RNA regulatory processes and protein processing were found to undergo increased AS during DR. Using a targeted RNAi screen, we identified a splicing mediator y41e3.11 that regulates a significant part of these AS events; consequently, knocking down this gene suppressed DR-mediated longevity. Concurrently, we found that the NMD genes are upregulated during DR and knocking down the key regulator, smg-2 (UPF1 homolog) suppressed DR life span. We show that knockdown of NMD during DR leads to a significant increase in the inclusion of PTC-containing introns and lengthening of the 3'UTR. Interestingly, mRNAs that are degraded by NMD are enriched for functions related to splicing, innate immunity and metabolism. Our study suggests that during DR, large-scale utilization of AS amplifies the proteome to handle diverse physiological remodelling required for enhanced longevity. As a consequence, dependence on NMD increases that also helps in fine-tuning the expression of metabolic and splicing mediators. AS-NMD may thus provide an energetically favourable level of dynamic gene expression control during times of energy restriction. Less...