Tissue-specific transcriptome profiling of Drosophila reveals roles for GATA transcription factors in longevity by dietary restriction.
Tissue-specific transcriptome profiling of Drosophila reveals roles for GATA transcription factors in longevity by dietary restriction.
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DOI：
10.1038/s41514-018-0024-4
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发表时间：
2018
影响因子：
5
通讯作者：
Piper MDW
中科院分区：
文献类型：
--
作者：
Dobson AJ;He X;Blanc E;Bolukbasi E;Feseha Y;Yang M;Piper MDW
饮食限制（DR）延长了动物的寿命，但增加了健康成本。这种现象取决于膳食必需氨基酸（EAAs）和TOR信号，它们发挥全身作用。然而，特定组织和细胞自主转录调节因子在DR表型的各个方面的作用尚不清楚。在寿命限制组织中操纵相关转录因子（TFs）可能会将DR的寿命益处与早期健康成本分开。在这里，我们系统地分析了受DR或低TOR影响的果蝇各器官的转录，并预测了调节性tf。我们预测并验证了进化保守的TFs GATA家族的作用，并确定了该信号在小鼠中的保守性。重要的是，将GATA TF srp的敲低限制在特定的果蝇组织中，再现了dr的好处，而不是代价。总之，我们的数据表明，GATA TF介导膳食氨基酸对寿命的影响，通过在特定组织中操纵它们，有可能获得eaa的健康益处，与寿命成本分离。人口老龄化是一个巨大的社会挑战，为寻找改善老年人健康的方法提供了动力。饮食限制（DR）是改善动物（从蠕虫到哺乳动物，也许还有人类）晚年健康的一种方法。这种效应在80多年前首次被观察到，但其潜在机制一直难以捉摸。在这项研究中，基因表达谱在果蝇遭受DR的不同组织中，并从这些结果预测了GATA转录因子蛋白的作用。减少GATA转录因子的表达改变了饮食对寿命的影响，将这种基因敲低到特定组织可以减少通常与寿命相关的副作用。因此，本研究预测，针对特定组织中的GATA转录因子可能会促进DR的收益，而不是成本。
Dietary restriction (DR) extends animal lifespan, but imposes fitness costs. This phenomenon depends on dietary essential amino acids (EAAs) and TOR signalling, which exert systemic effects. However, the roles of specific tissues and cell-autonomous transcriptional regulators in diverse aspects of the DR phenotype are unknown. Manipulating relevant transcription factors (TFs) specifically in lifespan-limiting tissues may separate the lifespan benefits of DR from the early-life fitness costs. Here, we systematically analyse transcription across organs of Drosophila subjected to DR or low TOR and predict regulatory TFs. We predict and validate roles for the evolutionarily conserved GATA family of TFs, and identify conservation of this signal in mice. Importantly, restricting knockdown of the GATA TF srp to specific fly tissues recapitulated the benefits but not the costs of DR. Together, our data indicate that the GATA TFs mediate effects of dietary amino acids on lifespan, and that by manipulating them in specific tissues it is possible to reap the fitness benefits of EAAs, decoupled from a cost to longevity. Ageing human populations present a huge societal challenge, providing motivation to find ways to improve health in old age. Dietary restriction (DR), is one way to improve late-life health of animals from worms to mammals, and perhaps humans. This effect was first oberved over 80 years ago, but the underlying mechanism has proven elusive. In this study, gene expression was profiled in diverse tissues of flies subjected to DR, and from these results a role for proteins called GATA transcription factors was predicted. Reducing expression of GATA transcription factors altered the effect of diet on lifespan, and targeting this knockdown to specific tissues reduced side-effects commonly associated with longevity. Therefore this study predicts that targeting GATA transcription factors in specific tissues may promote the benefits, but not costs, of DR.