A family of transcription factors that limit lifespan: ETS factors have conserved roles in longevity
A family of transcription factors that limit lifespan: ETS factors have conserved roles in longevity
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限制寿命的转录因子家族：ETS 因子在长寿中发挥保守作用
DOI：
10.1101/438879
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Dobson A
中科院分区：
文献类型：
--
作者：
Dobson A
人口平均年龄的增加以及随之而来的健康状况不佳的负担是我们这个时代的公共卫生危机之一。了解衰老过程的基本生物学可能有助于改善伴随衰老的病理学。衰老可以被调节，通常通过基因表达的变化，其中转录的调节起着关键作用。众所周知，叉头转录因子（TF）的活性可以延长寿命，但人们缺乏对促进寿命的更广泛转录网络的详细了解。本研究的重点是E二十六（ETS）家庭的TF。这个TF家族很大，在后生动物中保守，并且已知在发育和癌症中发挥作用，但其成员在衰老中的作用尚未得到广泛研究。在果蝇中，ETS转录抑制因子Aop和ETS转录激活因子Pnt与Foxo基因相互作用，激活Aop足以延长寿命。在这里，它表明，Aop和Foxo影响相关的基因表达程序。此外，Aop可以调节Foxo的转录输出，以根据启动子环境调节或协同Foxo活性，体外和体内都是如此。体内全基因组mRNA表达分析对Aop、Pnt或Foxo的反应表明，并进一步实验证实，三种TF的组合活性决定了代谢状态，Pnt活性的直接降低足以促进长寿。ETS因素在长寿中的作用不仅限于Pnt和Aop。在不同的细胞类型中，Ets 21 corEip 74 EF的敲低也延长了寿命，这表明在多种细胞环境中，寿命受到ETS结合位点转录的限制。降低C. elegansETS TFLin-1也延长了寿命，这一发现证实了该TF家族在衰老过程中的作用。总之，这些结果揭示了ETS家族的TF作为普遍的和进化上保守的长寿经纪人。
Increasing average population age, and the accompanying burden of ill health, is one of the public health crises of our time. Understanding the basic biology of the ageing process may help ameliorate the pathologies that characterise old age. Ageing can be modulated, often through changes in gene expression where regulation of transcription plays a pivotal role. Activities of Forkhead transcription factors (TFs) are known to extend lifespan, but detailed knowledge of the broader transcriptional networks that promote longevity is lacking. This study focuses on the E twenty-six (ETS) family of TFs. This family of TFs is large, conserved across metazoa, and known to play roles in development and cancer, but the role of its members in ageing has not been studied extensively. InDrosophila, an ETS transcriptional repressor,Aop, and an ETS transcriptional activator,Pnt, are known to genetically interact withFoxoand activatingAopis sufficient to extend lifespan. Here, it is shown thatAopandFoxoeffect a related gene-expression programme. Additionally,Aopcan modulateFoxo’s transcriptional output to moderate or synergise withFoxoactivity depending on promoter context, bothin vitroandin vivo.In vivogenome-wide mRNA expression analysis in response toAop,PntorFoxoindicated, and further experiments confirmed, that combinatorial activities of the three TFs dictate metabolic status, and that direct reduction ofPntactivity is sufficient to promote longevity. The role of ETS factors in longevity was not limited toPntandAop. Knockdown ofEts21corEip74EFin distinct cell types also extended lifespan, revealing that lifespan is limited by transcription from the ETS binding site in multiple cellular contexts. Reducing the activity of theC. elegansETS TFLin-1also extended lifespan, a finding that corroborates established evidence of roles of this TF family in ageing. Altogether, these results reveal the ETS family of TFs as pervasive and evolutionarily conserved brokers of longevity.
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