Identification and characterization of two functional variants in the human longevity gene FOXO3
Identification and characterization of two functional variants in the human longevity gene FOXO3
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DOI：
10.1038/s41467-017-02183-y
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发表时间：
2017-12-12
影响因子：
16.6
通讯作者：
Nebel, Almut
中科院分区：
文献类型：
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作者：
Flachsbart, Friederike;Dose, Janina;Nebel, Almut
FOXO3 一直被注释为人类长寿基因。然而，这种关联的功能变异和潜在机制仍然未知。在这里，我们对三个欧洲人群进行了 FOXO3 基因座的重测序和单核苷酸变异 (SNV) 基因分型。我们发现两个 FOXO3 SNV，rs12206094 和 rs4946935，与长寿最显着相关，并进一步表征了它们的功能。我们通过实验验证了计算机预测的转录因子（CTCF、SRF）与 SNV 的等位基因依赖性结合。具体来说，在荧光素酶报告基因检测中，两种变体的长寿等位基因都显示出相当大的增强子活性，而 IGF-1 处理可逆转这种活性。 eQTL 数据库搜索显示，等位基因还与各种人体组织中较高的 FOXO3 mRNA 表达相关，这与长寿模型生物体中的观察结果一致。总之，我们提供了 FOXO3 常见内含子变异与人类长寿之间功能联系的实验证据。
FOXO3 is consistently annotated as a human longevity gene. However, functional variants and underlying mechanisms for the association remain unknown. Here, we perform resequencing of the FOXO3 locus and single-nucleotide variant (SNV) genotyping in three European populations. We find two FOXO3 SNVs, rs12206094 and rs4946935, to be most significantly associated with longevity and further characterize them functionally. We experimentally validate the in silico predicted allele-dependent binding of transcription factors (CTCF, SRF) to the SNVs. Specifically, in luciferase reporter assays, the longevity alleles of both variants show considerable enhancer activities that are reversed by IGF-1 treatment. An eQTL database search reveals that the alleles are also associated with higher FOXO3 mRNA expression in various human tissues, which is in line with observations in long-lived model organisms. In summary, we present experimental evidence for a functional link between common intronic variants in FOXO3 and human longevity.