Changes in splicing factor expression are associated with advancing age in man
Changes in splicing factor expression are associated with advancing age in man
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DOI：
10.1016/j.mad.2013.05.006
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发表时间：
2013-09-01
影响因子：
5.3
通讯作者：
Harries, Lorna W.
中科院分区：
文献类型：
--
作者：
Holly, Alice C.;Melzer, David;Harries, Lorna W.
人类衰老与细胞可塑性和适应性下降有关。在人类中，随着年龄的增长，选择性剪接的变化已被报道，这可能是由于剪接因子表达的年龄相关的改变。我们确定是否关键剪接因子的mRNA表达随年龄的不同，通过微阵列分析血液从两个人群和qRT-PCR在衰老的原代成纤维细胞和内皮细胞。通过siRNA分析研究了剪接因子表达的潜在调节因子，在两个人群中，约三分之一的剪接因子表现出与年龄相关的转录表达变化。人类微阵列数据中共济失调毛细血管扩张症突变（ATM）转录本表达与剪接因子表达相关。衰老的原代成纤维细胞和内皮细胞也表现出剪接因子表达的改变，以及选择性剪接的变化。在原代成纤维细胞中靶向敲除ATM基因导致一些年龄反应性剪接因子转录本上调，我们得出结论，异构体比例和剪接因子表达在体内和体外随年龄而改变，ATM可能对一些剪接因子的表达具有抑制作用。这些研究结果首次表明，ATM，在DNA损伤反应的核心元素，是一个关键的调节剪接机制在人。（C）2013爱思唯尔爱尔兰有限公司。保留所有权利。
Human ageing is associated with decreased cellular plasticity and adaptability. Changes in alternative splicing with advancing age have been reported in man, which may arise from age-related alterations in splicing factor expression.We determined whether the mRNA expression of key splicing factors differed with age, by microarray analysis in blood from two human populations and by qRT-PCR in senescent primary fibroblasts and endothelial cells. Potential regulators of splicing factor expression were investigated by siRNA analysis.Approximately one third of splicing factors demonstrated age-related transcript expression changes in two human populations. Ataxia Telangiectasia Mutated (ATM) transcript expression correlated with splicing factor expression in human microarray data. Senescent primary fibroblasts and endothelial cells also demonstrated alterations in splicing factor expression, and changes in alternative splicing. Targeted knockdown of the ATM gene in primary fibroblasts resulted in up-regulation of some age-responsive splicing factor transcripts.We conclude that isoform ratios and splicing factor expression alters with age in vivo and in vitro, and that ATM may have an inhibitory role on the expression of some splicing factors. These findings suggest for the first time that ATM, a core element in the DNA damage response, is a key regulator of the splicing machinery in man. (C) 2013 Elsevier Ireland Ltd. All rights reserved.