Department of Biological Sciences, Southern Methodist University, 6501 Airline Rd, Dallas, TX 75205, USA.
Genetics. 2024 Feb 7;226(2). doi: 10.1093/genetics/iyad212.
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/ELAVL and mbl-1/Muscleblind, which in Caenorhabditis elegans display synthetic (nonadditive) lifespan defects: single mutants do not affect lifespan, but exc-7; mbl-1 double 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 the exc-7; mbl-1 lifespan phenotype. We identified 1 such gene, the ion transporter nhx-6, which is highly upregulated in double mutants. Overexpression of nhx-6 causes reduced lifespan, and deletion of nhx-6 in an exc-7; mbl-1 background 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.
转录因子对寿命的调控作用已经得到了很好的证实。最近，RNA 结合蛋白（RBPs）在调节寿命方面的作用也已经显现出来。在这两种情况下，一个主要的挑战是确定哪些调节靶标是负责观察到的寿命表型的功能。我们最近鉴定了一对神经元 RBPs，即 exc-7/ELAVL 和 mbl-1/Muscleblind，它们在秀丽隐杆线虫中表现出合成（非加性）寿命缺陷：单突变体不影响寿命，但 exc-7;mbl-1 双突变体的寿命明显缩短。这种强烈的合成表型为使用转录组学寻找潜在的因果靶标提供了机会，这些靶标受到合成调控。关注这些基因可以通过忽略仅在单突变体中改变的数百个基因，缩小我们的目标搜索范围，并提供一个可能负责双突变体表型的合成调控候选靶目标的候选名单。我们鉴定出一小部分在双突变体中合成失调的基因，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。我们鉴定出 1 个这样的基因，即离子转运蛋白 nhx-6，它在双突变体中高度上调。nhx-6 的过表达导致寿命缩短，而在 exc-7;mbl-1 背景下删除 nhx-6 部分恢复了寿命和健康寿命。这些结果表明，一对 RBPs 通过抑制离子转运蛋白的表达来介导寿命，为如何在转录组水平上剖析合成表型（包括寿命）以揭示潜在的因果基因提供了模板。
