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首页> 外文期刊>The journals of gerontology.Series A. Biological sciences and medical sciences >Cell-to-Cell Variation in Gene Expression for Cultured Human Cells Is Controlled in Trans by Diverse Genes: Implications for the Pathobiology of Aging
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Cell-to-Cell Variation in Gene Expression for Cultured Human Cells Is Controlled in Trans by Diverse Genes: Implications for the Pathobiology of Aging

机译：培养的人体细胞基因表达的细胞对细胞变异是通过各种基因控制的：对老化病原体学的影响

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Cell-to-cell variation in gene expression increases among homologous cells within multiple tissues during aging. We call this phenomenon variegated gene expression (VGE). Long, healthy life requires robust and coordinated gene expression. We posit that nature may have evolved VGE as a bet-hedging mechanism to protect reproductively active populations. The price we may pay is accelerated aging. That hypothesis will require the demonstration that genetic loci are capable of modulating degrees of VGE. While loci controlling VGE in yeast and genes controlling interindividual variation in gene expression in Caenorhabditis elegans have been identified, there has been no compelling evidence for the role of specific genetic loci in modulations of VGE of specific targets in humans. With the assistance of a core facility, we used a customized library of siRNA constructs to screen 1,195 human genes to identify loci contributing to the control of VGE of a gene with relevance to the biology of aging. We identified approximately 50 loci controlling VGE of the prolongevity gene, SIRT1. Because of its partial homology to FOXO3A, a variant of which is enriched in centenarians, our laboratory independently confirmed that the knockdown of FOXF2 greatly diminished VGE of SIRT1 but had little impact upon the VGE of WRN. While the role of these VGE-altering genes on aging in vivo remains to be determined, we hypothesize that some of these genes can be targeted to increase functionality during aging.
机译：衰老过程中，多个组织内同源细胞间基因表达的细胞间变异增加。我们称这种现象为杂色基因表达（VGE）。长寿、健康的生活需要强健、协调的基因表达。我们推测，大自然可能已经将VGE进化为一种赌注对冲机制，以保护繁殖活跃的种群。我们可能付出的代价是加速老龄化。这一假设需要证明基因座能够调节VGE的程度。虽然控制酵母中VGE的基因座和控制秀丽隐杆线虫基因表达个体间变异的基因已被确定，但还没有令人信服的证据表明特定基因座在人类特定目标的VGE调节中的作用。在核心设施的帮助下，我们使用定制的siRNA构建文库筛选1195个人类基因，以确定有助于控制与衰老生物学相关基因VGE的位点。我们确定了大约50个控制延长基因SIRT1的VGE的位点。由于FOXF2与FOXO3A的部分同源性（FOXO3A的一个变体富含百岁老人），我们的实验室独立证实，FOXF2的敲除大大降低了SIRT1的VGE，但对WRN的VGE几乎没有影响。虽然这些VGE改变基因在体内衰老中的作用仍有待确定，但我们假设其中一些基因可以在衰老过程中增加功能。

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