Lifespan extension by differential translation mediated by eIF-4G in C. elegans

线虫中 eIF-4G 介导的差异翻译延长寿命

• 批准号: 8794391
• 负责人: ARIC N ROGERS
• 金额: $ 24.14万
• 依托单位: MOUNT DESERT ISLAND BIOLOGICAL LAB
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8794391
• 关键词: 3' Untranslated Regions; Accounting; Address; Aging; Alternative Splicing; Animal Model; Attenuated; Binding; Bioinformatics; Biological; Biological Assay; Biological Models; Caenorhabditis elegans; Candidate Disease Gene; Characteristics; Computers; Data Set; Development; Diabetes Mellitus; Disease; Eukaryotic Initiation Factor-4G; Frequencies; Gene Expression Profile; Genes; Genetic; Genetic Epistasis; Genetic Translation; Goals; Health; Human; Length; Life; Longevity; Longevity Pathway; Maintenance; Malignant Neoplasms; Mammals; Mass Spectrum Analysis; Mediating; Mentors; Mentorship; Messenger RNA; Methods; MicroRNAs; Modeling; Monitor; Nematoda; Nerve Degeneration; Open Reading Frames; Orthologous Gene; Play; Process; Protein Biosynthesis; Proteins; Proteome; RNA Splicing; Regulation; Regulatory Element; Reporter; Research; Resistance; Ribosomes; Role; Scientist; Sequence Analysis; Small RNA; Source; Starvation; Testing; Transcript; Transgenic Animals; Translating; Translation Initiation; Translations; Untranslated Regions; Yeasts; abstracting; age related; aging gene; attenuation; base; biological adaptation to stress; cell type; computerized data processing; deep sequencing; genetic manipulation; genome-wide; in vivo; information gathering; mRNA Expression; novel; overexpression; tool

6. Project Summary / Abstract Although inhibition of translation initiation extends lifespan from yeast to mammals, the mechanism remains unknown. We showed that one of the most robust lifespan extension comes from suppression of ifg-1, the C. elegans ortholog of eukaryotic translation initiation factor (eIF)-4G, a factor that positively regulates translation. Previous studies have analyzed changes in total mRNA expression to investigate causes of lifespan changes under a number of different genetic and environmental conditions. However, other studies have shown large discrepancies between the transcriptome and proteome. I used translation state array analysis (TSAA), which accounts for post-transcriptional processing, to investigate changes upon direct modulation of translation by inhibiting ifg-1 expression. A large number of differentially translated mRNAs were found and ontological analysis revealed that upregulated genes included stress response genes and aging genes that are positive regulators of aging. Preliminary sequence analysis suggests that genes with preferrentially maintained expression contain conserved characteristics known to modulate translation. qRT- PCR and quantitative mass spectroscopy corroborate TSAA results. Hypothesis: in addition to reducing global rates of translation, suppression of ifg-1 results in preferential translation of mRNA associated with stress response and somatic maintenance based on mRNA composition. An epistasis screen of 50 translationally enhanced stress response genes showed 10 that are required for maximal lifespan extension when ifg-1 is inhibited. I intend to a) directly determine translation changes and the impact of overexpression for these seven genes using in vivo reporter constructs, b) analyze sequences for known or novel cis- regulatory elements and isolate microRNAs (miRNAs) associated with differentially translated mRNAs, and c) characterize the miRNA and cis-regulatory elements for their effects between conditions as well as their roles in lifespan modulation.

6。项目摘要 /摘要 尽管对翻译起始的抑制作用延长了寿命从酵母到哺乳动物，但该机制 仍然未知。我们表明，最强大的寿命延长之一来自对IFG-1的抑制 真核翻译起始因子（EIF）-4G的秀丽隐杆线虫直系同源物，一个积极调节的因素 翻译。先前的研究已经分析了总mRNA表达的变化，以研究 在许多不同的遗传和环境条件下，寿命变化。但是，其他研究 在转录组和蛋白质组之间显示出很大的差异。我使用了翻译状态阵列 分析（TSAA），该分析后处理后处理，以调查直接的变化 通过抑制IFG-1表达来调节翻译。大量差异翻译的mRNA是 发现和本体论分析表明，上调的基因包括应力反应基因和衰老 是衰老的积极调节因子的基因。初步序列分析表明，具有 优选维护的表达包含已知可以调节翻译的保守特征。 qrt- PCR和定量质谱证实了TSAA结果。假设：除了减少 全球翻译速率，抑制IFG-1会导致与mRNA相关的优先翻译 基于mRNA组成的压力反应和躯体维持。上学屏幕50 翻译增强的压力反应基因显示10个最大寿命延伸所需的是 当抑制IFG-1时。我打算a）直接确定翻译变化和过表达的影响 对于使用体内报告基因构建体的这七个基因，b）分析已知或新颖顺式的序列 与差分翻译的mRNA相关的调节元件和分离的microRNA（miRNA），c） 表征miRNA和顺式调节元素，以在条件及其角色之间的影响 在寿命调制中。

项目成果

A Novel Caenorhabditis Elegans Proteinopathy Model Shows Changes in mRNA Translational Frameshifting During Aging.

一种新的秀丽隐杆线虫蛋白病模型显示衰老过程中 mRNA 翻译移码的变化。

• DOI: 10.33594/000000067
• 发表时间: 2019
• 期刊: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
• 作者: Adamla,Frauke;Rollins,Jarod;Newsom,Matthew;Snow,Santina;Schosserer,Markus;Heissenberger,Clemens;Horrocks,Jordan;Rogers,AricN;Ignatova,Zoya
• 通讯作者: Ignatova,Zoya