Abstract
Alternative splicing (AS) coupled to nonsense-mediated decay (AS-NMD) is a conserved mechanism for post-transcriptional gene regulation. Here we show that, during dietary restriction (DR), AS is enhanced in Caenorhabditis elegans and mice. A splicing mediator hrpu-1 regulates a significant part of these AS events in C. elegans; knocking it down suppresses DR-mediated longevity. Concurrently, due to increased AS, NMD pathway genes are upregulated and knocking down UPF1 homologue smg-2 suppresses DR lifespan. Knockdown of NMD during DR significantly increases the inclusion of PTC-containing introns and the lengths of the 3′UTRs. Finally, we demonstrate that PHA-4/FOXA transcriptionally regulates the AS-NMD genes. Our study suggests that DR uses AS to amplify the proteome, supporting physiological remodelling required for enhanced longevity. This increases the dependence on NMD, but also helps fine-tune the expression of metabolic and splicing mediators. AS-NMD may thus provide an energetically favourable level of dynamic gene expression control during dietary restriction.
Highlights
Alternative splicing (AS) coupled to nonsense-mediated decay (AS-NMD) is a conserved mechanism for post-transcriptional gene regulation
Of the seven AS patterns known, we focussed on two types of AS events, namely, cassette exons and intron retention when analysing the day 3 data (Fig. 1)
In case of intron retention, we focussed on two terms, i.e., reads that mapped to the intron itself as well as to the skipping junction created when the intron is excised, while taking into account that the flanking exons are expressed
Summary
Alternative splicing (AS) coupled to nonsense-mediated decay (AS-NMD) is a conserved mechanism for post-transcriptional gene regulation. Our study suggests that DR uses AS to amplify the proteome, supporting physiological remodelling required for enhanced longevity This increases the dependence on NMD, and helps fine-tune the expression of metabolic and splicing mediators. Human studies have shown that around 92–94% of the genes are alternatively spliced,[13] and of these, 40% of AS events can generate in-frame premature termination codons (PTCs), which are natural targets of the nonsense-mediated decay (NMD) pathway, a post-transcriptional RNA surveillance mechanism[14, 15]. AS-NMD plays an important role in regulating the function of a gene by increasing the expression of a non-functional NMD-targeted isoform of the active gene, thereby decreasing the translation of the protein. DR entails a large-scale reprogramming of the cellular metabolic processes that supports the increased lifespan and requires an extensive transcriptional and post-transcriptional response[20, 22, 29, 30]
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