Longevity Genes Revealed by Integrative Analysis of Isoform-Specific daf-16/FoxO Mutants of Caenorhabditis elegans.
Longevity Genes Revealed by Integrative Analysis of Isoform-Specific daf-16/FoxO Mutants of Caenorhabditis elegans.
复制标题
长寿基因通过对秀丽隐杆线虫的同工型特异性DAF-16/FOXO突变体的综合分析揭示了寿命基因。
DOI：
10.1534/genetics.115.177998
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发表时间：
2015-10
期刊：
影响因子：
3.3
通讯作者：
Hu PJ
中科院分区：
文献类型：
--
作者：
Chen AT;Guo C;Itani OA;Budaitis BG;Williams TW;Hopkins CE;McEachin RC;Pande M;Grant AR;Yoshina S;Mitani S;Hu PJ
FoxO转录因子促进跨分类群的长寿。他们是如何做到这一点的，我们知之甚少。在线虫秀丽隐杆线虫中，FoxO转录因子β-16的A-和F-同种型在β-2胰岛素样生长因子受体（IGFR）信号传导减少的情况下延长寿命。为了阐明DAF-16/FoxO依赖性寿命延长的机制基础，我们对同种型特异性daf-16/FoxO突变体进行了整合分析。与先前的研究表明，在寿命控制中，DAF-16 F比DAF-16 A发挥更突出的作用相反，同种型特异性daf-16/FoxO突变体表型和全转录组分析显示，DAF-16 A在寿命控制、抗逆性和靶基因调控中比DAF-16 F起主导作用。这些数据集的整合使得能够优先考虑92个β-16/FoxO靶基因的子集用于功能询问。在检测的29个基因中，两个β-16A特异性靶基因显著影响寿命。保守基因gst-20中的功能缺失突变，其由DAF-16 A诱导，在daf-2/IGFR RNAi的背景下减少寿命延长，而不影响经受对照RNAi的动物的寿命。因此，gst-20促进了DAF-16/FoxO依赖性寿命。相反，srr-4（一种编码受fos-16 A抑制的七跨膜结构域受体家族成员的基因）的功能缺失突变延长了对照动物的寿命，表明fos-16/FoxO可能至少部分通过减少srr-4表达来延长寿命。我们发现的新的长寿基因强调了我们的综合策略的功效，同时提供了一个总体框架，以确定具体的下游基因调控事件，大大有助于转录因子的功能。由于FoxO转录因子在促进长寿方面具有保守的功能，并且可能在衰老相关疾病中失调，这些发现有望阐明动物衰老的基本原理。
FoxO transcription factors promote longevity across taxa. How they do so is poorly understood. In the nematode Caenorhabditis elegans, the A- and F-isoforms of the FoxO transcription factor DAF-16 extend life span in the context of reduced DAF-2 insulin-like growth factor receptor (IGFR) signaling. To elucidate the mechanistic basis for DAF-16/FoxO-dependent life span extension, we performed an integrative analysis of isoform-specific daf-16/FoxO mutants. In contrast to previous studies suggesting that DAF-16F plays a more prominent role in life span control than DAF-16A, isoform-specific daf-16/FoxO mutant phenotypes and whole transcriptome profiling revealed a predominant role for DAF-16A over DAF-16F in life span control, stress resistance, and target gene regulation. Integration of these datasets enabled the prioritization of a subset of 92 DAF-16/FoxO target genes for functional interrogation. Among 29 genes tested, two DAF-16A-specific target genes significantly influenced longevity. A loss-of-function mutation in the conserved gene gst-20, which is induced by DAF-16A, reduced life span extension in the context of daf-2/IGFR RNAi without influencing longevity in animals subjected to control RNAi. Therefore, gst-20 promotes DAF-16/FoxO-dependent longevity. Conversely, a loss-of-function mutation in srr-4, a gene encoding a seven-transmembrane-domain receptor family member that is repressed by DAF-16A, extended life span in control animals, indicating that DAF-16/FoxO may extend life span at least in part by reducing srr-4 expression. Our discovery of new longevity genes underscores the efficacy of our integrative strategy while providing a general framework for identifying specific downstream gene regulatory events that contribute substantially to transcription factor functions. As FoxO transcription factors have conserved functions in promoting longevity and may be dysregulated in aging-related diseases, these findings promise to illuminate fundamental principles underlying aging in animals.