Loss of circRNAs from the crh-1 gene extends the mean lifespan in Caenorhabditis elegans.

Autor: Knupp D; Department of Biology, University of Nevada, Reno, Reno, Nevada, USA., Jorgensen BG; Department of Biology, University of Nevada, Reno, Reno, Nevada, USA., Alshareef HZ; Department of Biology, University of Nevada, Reno, Reno, Nevada, USA., Bhat JM; Department of Biology, University of Nevada, Reno, Reno, Nevada, USA., Grubbs JJ; Department of Biology, University of Nevada, Reno, Reno, Nevada, USA., Miura P; Department of Biology, University of Nevada, Reno, Reno, Nevada, USA., van der Linden AM; Department of Biology, University of Nevada, Reno, Reno, Nevada, USA.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2022 Feb; Vol. 21 (2), pp. e13560. Date of Electronic Publication: 2022 Jan 31.
DOI: 10.1111/acel.13560
Abstrakt: Accumulation of circular RNAs (circRNAs) during aging occurs on a genome-wide level for multiple organisms, but its significance is unknown. Generating circRNA loss-of-function mutants is difficult because the vast majority of these RNAs are comprised of exons shared with protein-coding mRNAs. In Caenorhabditis elegans, most circRNAs were previously found to accumulate during aging. Two of the most abundant, age-accumulating circRNAs are generated from exon 4 of the crh-1 gene (circ-crh-1). Here, we found that the biogenesis of circ-crh-1 was regulated by the double-stranded RNA-binding protein ADR-1. We identified Reverse Complementary Match (RCM) sequences in introns flanking circ-crh-1. Using CRISPR-Cas9, we deleted the downstream RCM and found that this completely eliminated expression of the circRNA without affecting linear mRNA expression from the crh-1 gene. Remarkably, worms lacking circ-crh-1 exhibited a significantly longer mean lifespan. Lifespan was partially restored to wild type by expression of circ-crh-1 in neural tissues. Widespread transcriptome alterations in circ-crh-1 mutants were identified using RNA-Seq. Moving forward, intronic RCM deletion using CRISPR should be a widely applicable method to identify lifespan-regulating circRNAs in C. elegans.
(© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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