A combination of genomic approaches reveals the role of FOXO1a in regulating an oxidative stress response pathway.
A combination of genomic approaches reveals the role of FOXO1a in regulating an oxidative stress response pathway.
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DOI：
10.1371/journal.pone.0001670
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发表时间：
2008-02-27
期刊：
影响因子：
3.7
通讯作者：
Gilad Y
中科院分区：
文献类型：
--
作者：
de Candia P;Blekhman R;Chabot AE;Oshlack A;Gilad Y
虽然人类和黑猩猩之间的许多表型差异可能是由于基因调控的变化造成的，但目前只有少数重要的功能调控差异是已知的。作为识别在人类谱系中被重塑的转录途径的第一步，我们重点研究了一种转录因子FOXO1a，我们之前发现它在人类肝脏中上调表达，与其他三个灵长类物种相比。我们专注于这个基因，因为它在调节新陈代谢和延年益寿方面起着已知的作用。利用siRNA敲除后的表达谱和染色质免疫沉淀的组合，我们确定了FOXO1a的八个新的直接转录靶点。这套基因包括硫氧还蛋白相互作用蛋白(TXNIP)基因，其表达直接受到FOXO1a的抑制。硫氧还蛋白相互作用蛋白可以抑制硫氧还蛋白(Trx)的还原活性，从而阻碍细胞对氧化应激的反应，并影响寿命。我们的结果为反复观察到FOXO转录因子调控的差异影响寿命提供了解释。此外，我们还发现，与黑猩猩相比，TXNIP在人类中的表达下调，这与其直接抑制子FOXO1a在人类中的上调一致，并与两个物种之间的寿命差异一致。
While many of the phenotypic differences between human and chimpanzee may result from changes in gene regulation, only a handful of functionally important regulatory differences are currently known. As a first step towards identifying transcriptional pathways that have been remodeled in the human lineage, we focused on a transcription factor, FOXO1a, which we had previously found to be up-regulated in the human liver compared to that of three other primate species. We concentrated on this gene because of its known role in the regulation of metabolism and in longevity. Using a combination of expression profiling following siRNA knockdown and chromatin immunoprecipitation in a human liver cell line, we identified eight novel direct transcriptional targets of FOXO1a. This set includes the gene for thioredoxin-interacting protein (TXNIP), the expression of which is directly repressed by FOXO1a. The thioredoxin-interacting protein is known to inhibit the reducing activity of thioredoxin (TRX), thereby hindering the cellular response to oxidative stress and affecting life span. Our results provide an explanation for the repeated observations that differences in the regulation of FOXO transcription factors affect longevity. Moreover, we found that TXNIP is down-regulated in human compared to chimpanzee, consistent with the up-regulation of its direct repressor FOXO1a in humans, and with differences in longevity between the two species.
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DOI：
10.1196/annals.1323.027
发表时间：
2005-01-01
期刊：
LONGEVITY HEALTH SCIENCES: THE PHOENIX CONFERENCE
影响因子：
--
作者：
Cutler, RG
通讯作者：
Cutler, RG
影响因子：
3.3
作者：
HARVEY, PH;CLUTTONBROCK, TH
通讯作者：
CLUTTONBROCK, TH
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
9.8
作者：
Ludwig MZ;Palsson A;Alekseeva E;Bergman CM;Nathan J;Kreitman M
通讯作者：
Kreitman M
影响因子：
10.7
作者：
Dermitzakis, ET;Clark, AG
通讯作者：
Clark, AG