FOXO3 longevity interactome on chromosome 6.
FOXO3 longevity interactome on chromosome 6.
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DOI：
10.1111/acel.12625
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发表时间：
2017-10
期刊：
影响因子：
7.8
通讯作者：
Willcox BJ
中科院分区：
文献类型：
--
作者：
Donlon TA;Morris BJ;Chen R;Masaki KH;Allsopp RC;Willcox DC;Elliott A;Willcox BJ
FOXO3 与多个人群的长寿有关。通过对长寿个体进行 DNA 测序，我们鉴定了 FOXO3 中的所有单核苷酸多态性 (SNP)，并显示 41 个与长寿相关。其中 13 个预测了转录因子结合位点的改变。这些 SNP 似乎通过 RNA 聚合酶 II 结合染色质环与 FOXO3 启动子中的位点进行物理接触，并且可能作为顺式调控单元一起发挥作用。 SNP 在亚洲人群中表现出高度的 LD，它们定义了相对常见的特定长寿单倍型。这种单倍型在白人中较少见，在非洲人中几乎不存在。我们通过 CCCTC 结合因子锌指蛋白 (CTCF) 结合位点的长距离物理接触，在染色体 6q21 上超过 7.3 Mb 的距离，确定了 FOXO3 和 46 个邻近基因之间的远程接触点。当被细胞应激激活时，我们观察到 FOXO3 向邻近基因的运动。 FOXO3 位于 6 号染色体这一早期复制且高度保守的同线区域的中心。因此，除了作为调节全基因组基因表达的转录因子的作用外，FOXO3 还可以在基因组水平上发挥作用，通过拓扑相关结构域在染色质构象中的中心位置来帮助调节邻近基因。我们认为 6 号染色体上的 FOXO3“相互作用组”是定义衰老中心的染色质结构域。更全面地了解这些邻近基因的功能可能有助于阐明 FOXO3 变体促进长寿和健康衰老的机制。
FOXO3 has been implicated in longevity in multiple populations. By DNA sequencing in long‐lived individuals, we identified all single nucleotide polymorphisms (SNPs) in FOXO3 and showed 41 were associated with longevity. Thirteen of these had predicted alterations in transcription factor binding sites. Those SNPs appeared to be in physical contact, via RNA polymerase II binding chromatin looping, with sites in the FOXO3 promoter, and likely function together as a cis‐regulatory unit. The SNPs exhibited a high degree of LD in the Asian population, in which they define a specific longevity haplotype that is relatively common. The haplotype was less frequent in whites and virtually nonexistent in Africans. We identified distant contact points between FOXO3 and 46 neighboring genes, through long‐range physical contacts via CCCTC‐binding factor zinc finger protein (CTCF) binding sites, over a 7.3 Mb distance on chromosome 6q21. When activated by cellular stress, we visualized movement of FOXO3 toward neighboring genes. FOXO3 resides at the center of this early‐replicating and highly conserved syntenic region of chromosome 6. Thus, in addition to its role as a transcription factor regulating gene expression genomewide, FOXO3 may function at the genomic level to help regulate neighboring genes by virtue of its central location in chromatin conformation via topologically associated domains. We believe that the FOXO3 ‘interactome’ on chromosome 6 is a chromatin domain that defines an aging hub. A more thorough understanding of the functions of these neighboring genes may help elucidate the mechanisms through which FOXO3 variants promote longevity and healthy aging.
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影响因子：
13.1
作者：
Chung WH;Dao RL;Chen LK;Hung SI
通讯作者：
Hung SI
DOI：
10.1038/nrg3454
发表时间：
2013-06
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
7
作者：
Boyle AP;Hong EL;Hariharan M;Cheng Y;Schaub MA;Kasowski M;Karczewski KJ;Park J;Hitz BC;Weng S;Cherry JM;Snyder M
通讯作者：
Snyder M
万能福克斯：揭开Foxo蛋白在衰老和寿命中的作用。
影响因子：
7.8
作者：
Martins R;Lithgow GJ;Link W
通讯作者：
Link W
DOI：
10.1093/bioinformatics/bts199
发表时间：
2012-06-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Kearse M;Moir R;Wilson A;Stones-Havas S;Cheung M;Sturrock S;Buxton S;Cooper A;Markowitz S;Duran C;Thierer T;Ashton B;Meintjes P;Drummond A
通讯作者：
Drummond A