Abstract
SummaryCircular RNAs (circRNAs) are abundant and accumulate with age in neurons of diverse species. However, only few circRNAs have been functionally characterized, and their role during aging has not been addressed. Here, we use transcriptome profiling during aging and find that accumulation of circRNAs is slowed down in long-lived insulin mutant flies. Next, we characterize the in vivo function of a circRNA generated by the sulfateless gene (circSfl), which is consistently upregulated, particularly in the brain and muscle, of diverse long-lived insulin mutants. Strikingly, lifespan extension of insulin mutants is dependent on circSfl, and overexpression of circSfl alone is sufficient to extend the lifespan. Moreover, circSfl is translated into a protein that shares the N terminus and potentially some functions with the full-length Sfl protein encoded by the host gene. Our study demonstrates that insulin signaling affects global circRNA accumulation and reveals an important role of circSfl during aging in vivo.
Highlights
Circular RNAs were originally identified more than 30 years ago, but for a long time they were thought to be by-products of the mRNA splicing process without a specific function; they were not investigated further (Grabowski et al, 1981; Capel et al, 1993; Nigro et al, 1991; Cocquerelle et al, 1993)
CircRNA Accumulation with Age in Neuronal Tissue Is Slowed Down in Insulin Mutants circRNAs accumulate with age in various organisms (Cortes-Lopez et al, 2018; Gruner et al, 2016; Westholm et al, 2014; Hall et al, 2017)
CircSfl Is Upregulated in Different Long-Lived Insulin Mutant Flies we looked at individual circRNAs that were differentially regulated in dilp 2-3,5 mutants independent of the host gene (Data S2) because this would suggest that regulation of the circRNA is specific and not merely co-regulation with the host gene
Summary
Circular RNAs (circRNAs) were originally identified more than 30 years ago, but for a long time they were thought to be by-products of the mRNA splicing process without a specific function; they were not investigated further (Grabowski et al, 1981; Capel et al, 1993; Nigro et al, 1991; Cocquerelle et al, 1993). CircRNAs have been discovered in fungi, protists, and plants (Wang et al, 2014); C. elegans (Memczak et al, 2013); Drosophila (Salzman et al, 2013); mice (Jeck et al, 2013); and humans (Salzman et al, 2012). CircRNAs are enriched in neuronal tissues such as Drosophila heads (Westholm et al, 2014) and the mammalian brain (Rybak-Wolf et al, 2015). CircRNAs have been shown to accumulate with age in C. elegans (Cortes-Lopez et al, 2018), in Drosophila heads and photoreceptor neurons (Westholm et al, 2014; Hall et al, 2017), and in the mouse cortex and hippocampus but not in mouse heart tissue (Gruner et al, 2016). A function of circRNAs in the aging process has not yet been revealed
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