A pair of RNA binding proteins inhibit ion transporter expression to maintain lifespan.
A pair of RNA binding proteins inhibit ion transporter expression to maintain lifespan.
复制标题
一对 RNA 结合蛋白抑制离子转运蛋白的表达以维持寿命。
DOI：
10.1101/2023.05.10.540279
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Norris,Adam
中科院分区：
文献类型：
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作者：
Napier-Jameson,Rebekah;Marx,Olivia;Norris,Adam
转录因子对寿命的调节已经很好地建立。最近，RNA结合蛋白（RBP）在调节寿命中的作用也出现了。在这两种情况下，一个主要的挑战是确定哪些调控目标是功能上负责观察到的寿命表型。我们最近发现了一对神经元RBP，exc-7/ELAV和mbl-1/Muscleblind，它们在秀丽隐杆线虫中显示出合成的（非加性的）寿命缺陷：单突变体不影响寿命，但exc-7; mbl-1双突变体强烈降低寿命。这样一个强大的合成表型代表了一个机会，使用转录组学来寻找潜在的致病目标，是合成调节。关注这些基因将使我们能够通过忽略仅在单突变体中改变的数百个基因来缩小我们的目标搜索，并提供可能负责双突变表型的合成调控候选靶点的短名单。我们在双突变体中鉴定了少数基因的合成失调，并系统地测试了每个候选基因对exc-7; mbl-1寿命表型的功能贡献。我们确定了一个这样的基因，离子转运蛋白HX-6，这是高度上调的双突变体。nhx-6的过表达导致寿命缩短，而nhx-6在anexc-7; mbl-1背景中的缺失部分恢复了寿命和健康期。总之，这些结果揭示了一对RBP部分通过抑制离子转运蛋白的表达来介导寿命，并为如何在转录组水平上解剖合成表型（包括寿命）以揭示潜在的致病基因提供了模板。
Regulation of lifespan by transcription factors has been well established. More recently, a role for RNA binding proteins (RBPs) in regulating lifespan has also emerged. In both cases, a major challenge is to determine which regulatory targets are functionally responsible for the observed lifespan phenotype. We recently identified a pair of neuronal RBPs,exc-7/ELAVLandmbl-1/Muscleblind, which inCaenorhabditis elegansdisplay synthetic (nonadditive) lifespan defects: single mutants do not affect lifespan, butexc-7; mbl-1double mutants have strongly reduced lifespan. Such a strong synthetic phenotype represented an opportunity to use transcriptomics to search for potential causative targets that are synthetically regulated. Focus on such genes would allow us to narrow our target search by ignoring the hundreds of genes altered only in single mutants, and provide a shortlist of synthetically regulated candidate targets that might be responsible for the double mutant phenotype. We identified a small handful of genes synthetically dysregulated in double mutants and systematically tested each candidate gene for functional contribution to theexc-7; mbl-1lifespan phenotype. We identified 1 such gene, the ion transporternhx-6, which is highly upregulated in double mutants. Overexpression ofnhx-6causes reduced lifespan, and deletion ofnhx-6in anexc-7; mbl-1background partially restores both lifespan and healthspan. Together, these results reveal that a pair of RBPs mediate lifespan in part by inhibiting expression of an ion transporter, and provide a template for how synthetic phenotypes (including lifespan) can be dissected at the transcriptomic level to reveal potential causative genes.