High-resolution profiling of stationary-phase survival reveals yeast longevity factors and their genetic interactions.
High-resolution profiling of stationary-phase survival reveals yeast longevity factors and their genetic interactions.
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DOI：
10.1371/journal.pgen.1004168
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发表时间：
2014-02
期刊：
影响因子：
4.5
通讯作者：
Deluna A
中科院分区：
文献类型：
--
作者：
Garay E;Campos SE;González de la Cruz J;Gaspar AP;Jinich A;Deluna A
寿命受到大量保守蛋白质和基因调控途径的影响。在这里，我们介绍了一种策略，系统地发现这些长寿因素在酿酒酵母和评分的遗传相互作用（上位性）这些因素。具体来说，我们开发了一种自动化的基于竞争的测定方法，用于时间寿命，定义为酵母菌群的稳定期存活，并使用它以前所未有的定量分辨率对5，600多个单基因或双基因敲除进行表型分析。我们发现，14%的可行的酵母突变株在其静止期生存的影响;真阳性的时间顺序寿命因素的程度估计占文化通风和适应性再生长的影响。我们表明，通过饮食限制延长寿命取决于Swr 1组蛋白交换复合物，自噬和脂质稳态因子Arv 1之间的功能联系对细胞寿命有影响。重要的是，我们描述了第一个基于衰老表型的遗传相互作用网络，它成功地概括了核心自噬机制，并证实了人类肿瘤抑制因子PTEN同源物在酵母寿命和磷脂酰肌醇磷酸代谢中的作用。我们对长寿因素及其遗传相互作用的定量分析为衰老细胞的基因网络相互作用提供了见解。芽殖酵母酿酒酵母已成为衰老遗传分析的重要模型，对酵母细胞中这一过程的了解增强了我们对包括人类在内的其他生物体衰老的理解。即使在酵母中，我们对决定寿命的基因的数量和身份的了解也是有限的，我们仍然缺乏对不同遗传衰老因素如何共同作用的总体了解。在这里，使用一种创新的敏感技术，我们已经确定了酵母单基因和双基因敲除突变体的稳定期生存的特征，以筛选控制时序老化的基因，并对这些基因之间的遗传相互作用进行评分。我们的研究结果表明，基因组的一个重要部分（14%）有助于调节寿命，包括以前与这种表型无关的基因和途径。我们还构建了一个遗传相互作用图，概括了寿命决定途径，并强调了自噬机制与磷脂酰肌醇磷酸和脂质稳态途径之间的遗传关联。我们的研究不仅提供了酵母衰老基因的准确目录，而且还提供了衰老细胞基因网络布线的图片。
Lifespan is influenced by a large number of conserved proteins and gene-regulatory pathways. Here, we introduce a strategy for systematically finding such longevity factors in Saccharomyces cerevisiae and scoring the genetic interactions (epistasis) among these factors. Specifically, we developed an automated competition-based assay for chronological lifespan, defined as stationary-phase survival of yeast populations, and used it to phenotype over 5,600 single- or double-gene knockouts at unprecedented quantitative resolution. We found that 14% of the viable yeast mutant strains were affected in their stationary-phase survival; the extent of true-positive chronological lifespan factors was estimated by accounting for the effects of culture aeration and adaptive regrowth. We show that lifespan extension by dietary restriction depends on the Swr1 histone-exchange complex and that a functional link between autophagy and the lipid-homeostasis factor Arv1 has an impact on cellular lifespan. Importantly, we describe the first genetic interaction network based on aging phenotypes, which successfully recapitulated the core-autophagy machinery and confirmed a role of the human tumor suppressor PTEN homologue in yeast lifespan and phosphatidylinositol phosphate metabolism. Our quantitative analysis of longevity factors and their genetic interactions provides insights into the gene-network interactions of aging cells. The budding yeast Saccharomyces cerevisiae has emerged as an important model for the genetic analysis of aging, and insights gained about this process in yeast cells enhance our understanding of aging in other organisms, including humans. Even in yeast, our knowledge of the number and identity of the genes that determine lifespan is limited and we are still lacking a general picture of how different genetic aging factors work together. Here, using an innovative sensitive technique, we have characterized the stationary-phase survival of yeast single- and double-gene knockout mutants to screen for genes that control chronological aging and to score the genetic interactions among these genes. Our results showed that an important fraction (14%) of the genome contributes to the regulation of lifespan, including genes and pathways that had not been previously associated to this phenotype. We also constructed a genetic interaction map which recapitulated lifespan-determining pathways and highlighted genetic associations between the autophagy machinery and the phosphatidylinositol-phosphate and lipid-homeostasis pathways. Our study provides not only an accurate catalogue of yeast aging genes, but also a picture of the gene-network wiring of aging cells.
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影响因子：
4.5
作者：
Fabrizio P;Hoon S;Shamalnasab M;Galbani A;Wei M;Giaever G;Nislow C;Longo VD
通讯作者：
Longo VD
影响因子：
7.8
作者：
Alvers AL;Fishwick LK;Wood MS;Hu D;Chung HS;Dunn WA Jr;Aris JP
通讯作者：
Aris JP
影响因子：
3.3
作者：
Gresham, David;Boer, Viktor M.;Botstein, David
通讯作者：
Botstein, David
DOI：
10.1073/pnas.97.23.12672
发表时间：
2000-11-07
影响因子：
11.1
作者：
Heymont, J;Berenfeld, L;Engebrecht, J
通讯作者：
Engebrecht, J
DOI：
10.1083/jcb.200604072
发表时间：
2006-07-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Allen C;Büttner S;Aragon AD;Thomas JA;Meirelles O;Jaetao JE;Benn D;Ruby SW;Veenhuis M;Madeo F;Werner-Washburne M
通讯作者：
Werner-Washburne M