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Extreme longevity variants at the FOXO3 locus may moderate FOXO3 isoform levels

The rs2802292, rs2764264 and rs13217795 variants of FOXO3 have been associated with extreme longevity in multiple human populations, but the mechanisms underpinning this remain unclear. We aimed to characterise potential effects of longevity-associated variation on the expression and mRNA processing...

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Autores principales: Frankum, Ryan, Jameson, Tom S. O., Knight, Bridget A., Stephens, Francis B., Wall, Benjamin T., Donlon, Timothy A., Torigoe, Trevor, Willcox, Bradley J., Willcox, D. Craig, Allsopp, Richard C., Harries, Lorna W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9135902/
https://www.ncbi.nlm.nih.gov/pubmed/34436732
http://dx.doi.org/10.1007/s11357-021-00431-0
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author Frankum, Ryan
Jameson, Tom S. O.
Knight, Bridget A.
Stephens, Francis B.
Wall, Benjamin T.
Donlon, Timothy A.
Torigoe, Trevor
Willcox, Bradley J.
Willcox, D. Craig
Allsopp, Richard C.
Harries, Lorna W.
author_facet Frankum, Ryan
Jameson, Tom S. O.
Knight, Bridget A.
Stephens, Francis B.
Wall, Benjamin T.
Donlon, Timothy A.
Torigoe, Trevor
Willcox, Bradley J.
Willcox, D. Craig
Allsopp, Richard C.
Harries, Lorna W.
author_sort Frankum, Ryan
collection PubMed
description The rs2802292, rs2764264 and rs13217795 variants of FOXO3 have been associated with extreme longevity in multiple human populations, but the mechanisms underpinning this remain unclear. We aimed to characterise potential effects of longevity-associated variation on the expression and mRNA processing of the FOXO3 gene. We performed a comprehensive assessment of FOXO3 isoform usage across a wide variety of human tissues and carried out a bioinformatic analysis of the potential for longevity-associated variants to disrupt regulatory regions involved in isoform choice. We then related the expression of full length and 5′ truncated FOXO3 isoforms to rs13217795 genotype in peripheral blood and skeletal muscle from individuals of different rs13217795 genotypes. FOXO3 isoforms displayed considerable tissue specificity. We determined that rs13231195 and its tightly aligned proxy variant rs9400239 may lie in regulatory regions involved in isoform choice. The longevity allele at rs13217795 was associated with increased levels of full length FOXO3 isoforms in peripheral blood and a decrease in truncated FOXO3 isoforms in skeletal muscle RNA. We suggest that the longevity effect of FOXO3 SNPs may in part derive from a shift in isoform usage in skeletal muscle away from the production of 5′ truncated FOXO3 isoforms lacking a complete forkhead DNA binding domain, which may have compromised functionality. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-021-00431-0.
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spelling pubmed-91359022022-05-28 Extreme longevity variants at the FOXO3 locus may moderate FOXO3 isoform levels Frankum, Ryan Jameson, Tom S. O. Knight, Bridget A. Stephens, Francis B. Wall, Benjamin T. Donlon, Timothy A. Torigoe, Trevor Willcox, Bradley J. Willcox, D. Craig Allsopp, Richard C. Harries, Lorna W. GeroScience Original Article The rs2802292, rs2764264 and rs13217795 variants of FOXO3 have been associated with extreme longevity in multiple human populations, but the mechanisms underpinning this remain unclear. We aimed to characterise potential effects of longevity-associated variation on the expression and mRNA processing of the FOXO3 gene. We performed a comprehensive assessment of FOXO3 isoform usage across a wide variety of human tissues and carried out a bioinformatic analysis of the potential for longevity-associated variants to disrupt regulatory regions involved in isoform choice. We then related the expression of full length and 5′ truncated FOXO3 isoforms to rs13217795 genotype in peripheral blood and skeletal muscle from individuals of different rs13217795 genotypes. FOXO3 isoforms displayed considerable tissue specificity. We determined that rs13231195 and its tightly aligned proxy variant rs9400239 may lie in regulatory regions involved in isoform choice. The longevity allele at rs13217795 was associated with increased levels of full length FOXO3 isoforms in peripheral blood and a decrease in truncated FOXO3 isoforms in skeletal muscle RNA. We suggest that the longevity effect of FOXO3 SNPs may in part derive from a shift in isoform usage in skeletal muscle away from the production of 5′ truncated FOXO3 isoforms lacking a complete forkhead DNA binding domain, which may have compromised functionality. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11357-021-00431-0. Springer International Publishing 2021-08-26 /pmc/articles/PMC9135902/ /pubmed/34436732 http://dx.doi.org/10.1007/s11357-021-00431-0 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Frankum, Ryan
Jameson, Tom S. O.
Knight, Bridget A.
Stephens, Francis B.
Wall, Benjamin T.
Donlon, Timothy A.
Torigoe, Trevor
Willcox, Bradley J.
Willcox, D. Craig
Allsopp, Richard C.
Harries, Lorna W.
Extreme longevity variants at the FOXO3 locus may moderate FOXO3 isoform levels
title Extreme longevity variants at the FOXO3 locus may moderate FOXO3 isoform levels
title_full Extreme longevity variants at the FOXO3 locus may moderate FOXO3 isoform levels
title_fullStr Extreme longevity variants at the FOXO3 locus may moderate FOXO3 isoform levels
title_full_unstemmed Extreme longevity variants at the FOXO3 locus may moderate FOXO3 isoform levels
title_short Extreme longevity variants at the FOXO3 locus may moderate FOXO3 isoform levels
title_sort extreme longevity variants at the foxo3 locus may moderate foxo3 isoform levels
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9135902/
https://www.ncbi.nlm.nih.gov/pubmed/34436732
http://dx.doi.org/10.1007/s11357-021-00431-0
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