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极端长寿变体在 FOXO3 基因座可能调节 FOXO3 同工型水平。

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

机构信息

Institute of Biomedical and Clinical Science, University of Exeter Medical School, Barrack Road, Exeter, EX2 5DW, UK.

College of Life and Environmental Sciences, University of Exeter, Exeter, UK.

出版信息

Geroscience. 2022 Apr;44(2):1129-1140. doi: 10.1007/s11357-021-00431-0. Epub 2021 Aug 26.

DOI:10.1007/s11357-021-00431-0
PMID:34436732
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9135902/
Abstract

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.

摘要

rs2802292、rs2764264 和 rs13217795 这三种 FOXO3 变体与多种人类群体中的极端长寿有关，但支持这一现象的机制尚不清楚。我们旨在研究与长寿相关的变异对 FOXO3 基因表达和 mRNA 处理的潜在影响。我们全面评估了 FOXO3 同工型在多种人类组织中的使用情况，并对与长寿相关的变异可能破坏参与同工型选择的调节区域进行了生物信息学分析。然后，我们将全长和 5'截断 FOXO3 同工型的表达与不同 rs13217795 基因型个体的外周血和骨骼肌中的 rs13217795 基因型相关联。FOXO3 同工型表现出相当大的组织特异性。我们确定 rs13231195 及其紧密排列的替代变体 rs9400239 可能位于参与同工型选择的调节区域。rs13217795 中的长寿等位基因与外周血中全长 FOXO3 同工型水平的升高有关，与骨骼肌 RNA 中截断 FOXO3 同工型的减少有关。我们认为，FOXO3 SNP 的长寿效应可能部分源于骨骼肌中同工型使用的转变，远离产生缺乏完整叉头 DNA 结合域的 5'截断 FOXO3 同工型，这可能会损害其功能。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f1b/9135902/f82483ba88d7/11357_2021_431_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f1b/9135902/fac5c92d870b/11357_2021_431_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f1b/9135902/314e37abbbc2/11357_2021_431_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f1b/9135902/28a2ac10e80f/11357_2021_431_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f1b/9135902/d42bae6283ae/11357_2021_431_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f1b/9135902/f82483ba88d7/11357_2021_431_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f1b/9135902/fac5c92d870b/11357_2021_431_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f1b/9135902/314e37abbbc2/11357_2021_431_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f1b/9135902/28a2ac10e80f/11357_2021_431_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f1b/9135902/d42bae6283ae/11357_2021_431_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2f1b/9135902/f82483ba88d7/11357_2021_431_Fig5_HTML.jpg

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