Longevity is determined by ETS transcription factors in multiple tissues and diverse species [FxAxP]

Ageing populations pose one of the main public health crises of our time. Reprogramming gene expression by altering the activities of sequence-specific transcription factors (TF) can ameliorate deleterious effects of age. Here we explore how a circuit of TFs coordinates pro-longevity transcriptional outcomes, which reveals a multi-tissue and multi-species role for an entire protein family: the E-twenty-six (ETS) TFs. In Drosophila, reduced insulin/IGF signalling (IIS) extends lifespan by coordinating activation of Aop, an ETS transcriptional repressor, and Foxo, a Forkhead transcriptional activator. Aop and Foxo bind the same genomic loci, and we show that, individually, they effect similar transcriptional programmes in vivo. In combination, Aop can both moderate or synergise with Foxo, dependent on promoter context. Moreover, Foxo and Aop oppose the activities of Pnt, an ETS transcriptional activator, effecting a transcriptomic programme that correlates lifespan outcomes. Directly limiting Pnt extended lifespan, suggesting this is how Aop and Foxo promote longevity. The lifespan-limiting role of Pnt appears to be balanced by a requirement for metabolic regulation in young flies, in which the Aop-Pnt-Foxo circuit determines nutrient storage, and Pnt regulates lipolysis and responses to nutrient stress. Molecular functions are conserved amongst ETS TFs, suggesting others may also affect ageing. We show that Ets21C limits lifespan, functioning in the same genetic network as Foxo and IIS. Other ETS TFs appear to play roles in fly ageing in multiple contexts, since inhibiting the majority of the family in intestine, adipose or neurons extended lifespan. We expand the repertoire of lifespan-limiting ETS TFs in C. elegans, confirming their conserved function in ageing. Altogether this study reveals that roles of ETS TFs in physiology and lifespan are conserved throughout the family, both within and between species. foxo, aopACT and pntP1 overexpression in S106 D. melanogaster, polyA RNAseq.

人口老龄化是我们这个时代最主要的公共卫生危机之一。通过改变序列特异性转录因子（sequence-specific transcription factor, TF）的活性来重编程基因表达，可缓解衰老带来的有害影响。本研究探讨了转录因子环路如何协调促长寿的转录调控结果，由此揭示了整个蛋白家族——E twenty-six（ETS）转录因子（TF）——在多组织、跨物种中的保守作用。在果蝇中，减弱的胰岛素/IGF信号通路（insulin/IGF signalling, IIS）通过协同激活ETS家族转录抑制因子Aop与叉头框转录激活因子Foxo，进而延长寿命。Aop与Foxo可结合相同的基因组位点，本研究证实二者单独作用时，在体内可诱导相似的转录程序。当二者联合发挥作用时，Aop可根据启动子背景分别介导调控作用或与Foxo产生协同效应。此外，Foxo与Aop可拮抗ETS转录激活因子Pnt的活性，由此构建的转录组程序与寿命表型密切相关。直接抑制Pnt可延长果蝇寿命，这表明Aop与Foxo正是通过该途径促进长寿。Pnt的限寿作用似乎会受到年轻果蝇代谢调控需求的制衡：在年轻个体中，Aop-Pnt-Foxo环路决定营养储存，而Pnt则调控脂解作用与营养应激应答。ETS家族转录因子的分子功能在进化中保守，提示该家族其他成员也可能参与衰老调控。本研究证实，Ets21C可发挥限寿作用，其功能与Foxo及IIS处于同一遗传网络中。在果蝇的肠道、脂肪组织或神经元中抑制绝大多数ETS家族成员均可延长寿命，表明其他ETS转录因子在果蝇衰老的多种情境中均发挥调控作用。我们还在秀丽隐杆线虫（Caenorhabditis elegans, C. elegans）中拓展了限寿ETS转录因子的功能谱系，证实了其在衰老过程中的保守功能。综上，本研究表明，ETS转录因子在生理功能与寿命调控中的作用在该家族内部以及物种间均具有保守性。本实验在S106品系黑腹果蝇（Drosophila melanogaster, D. melanogaster）中开展了foxo、aopACT与pntP1的过表达，并进行了polyA RNA测序（polyA RNAseq）。