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

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 Ca...

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Autores principales: Knupp, David, Jorgensen, Brian G., Alshareef, Hussam Z., Bhat, Jaffar M., Grubbs, Jeremy J., Miura, Pedro, van der Linden, Alexander M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8844124/
https://www.ncbi.nlm.nih.gov/pubmed/35102684
http://dx.doi.org/10.1111/acel.13560
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author Knupp, David
Jorgensen, Brian G.
Alshareef, Hussam Z.
Bhat, Jaffar M.
Grubbs, Jeremy J.
Miura, Pedro
van der Linden, Alexander M.
author_facet Knupp, David
Jorgensen, Brian G.
Alshareef, Hussam Z.
Bhat, Jaffar M.
Grubbs, Jeremy J.
Miura, Pedro
van der Linden, Alexander M.
author_sort Knupp, David
collection PubMed
description 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.
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spelling pubmed-88441242022-02-24 Loss of circRNAs from the crh‐1 gene extends the mean lifespan in Caenorhabditis elegans Knupp, David Jorgensen, Brian G. Alshareef, Hussam Z. Bhat, Jaffar M. Grubbs, Jeremy J. Miura, Pedro van der Linden, Alexander M. Aging Cell Short Communication 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. John Wiley and Sons Inc. 2022-01-31 2022-02 /pmc/articles/PMC8844124/ /pubmed/35102684 http://dx.doi.org/10.1111/acel.13560 Text en © 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Short Communication
Knupp, David
Jorgensen, Brian G.
Alshareef, Hussam Z.
Bhat, Jaffar M.
Grubbs, Jeremy J.
Miura, Pedro
van der Linden, Alexander M.
Loss of circRNAs from the crh‐1 gene extends the mean lifespan in Caenorhabditis elegans
title Loss of circRNAs from the crh‐1 gene extends the mean lifespan in Caenorhabditis elegans
title_full Loss of circRNAs from the crh‐1 gene extends the mean lifespan in Caenorhabditis elegans
title_fullStr Loss of circRNAs from the crh‐1 gene extends the mean lifespan in Caenorhabditis elegans
title_full_unstemmed Loss of circRNAs from the crh‐1 gene extends the mean lifespan in Caenorhabditis elegans
title_short Loss of circRNAs from the crh‐1 gene extends the mean lifespan in Caenorhabditis elegans
title_sort loss of circrnas from the crh‐1 gene extends the mean lifespan in caenorhabditis elegans
topic Short Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8844124/
https://www.ncbi.nlm.nih.gov/pubmed/35102684
http://dx.doi.org/10.1111/acel.13560
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