Exploring the connections between translation and mRNA decay

探索翻译和 mRNA 衰变之间的联系

• 批准号: 10454935
• 负责人: Olivia Selfridge Rissland
• 金额: $ 38.21万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454935
• 关键词: Address; Affect; Area; Binding Proteins; Cells; Codon Nucleotides; Collection; Defect; Development; Disease; Drosophila genus; Embryonic Development; Event; Gene Expression; Genes; Genetic; Genetic Transcription; Human; Lead; Life Cycle Stages; Link; Malignant Neoplasms; Mediating; Messenger RNA; Modeling; Molecular Biology; Nerve Degeneration; Organism; Outcome; Post-Transcriptional Regulation; Proteins; Repression; Research; Role; System; Transcription Repressor; Translation Initiation; Translational Repression; Translations; Work; computerized tools; genome-wide; human disease; improved; infancy; insight; mRNA Decay; mRNA Stability; mRNA decapping; transcriptome

SUMMARY It has been recognized for decades that post-transcriptional regulation is as important as transcription for controlling gene expression, but much of post-transcriptional regulation is a black box. Alterations in post-transcriptional regulation can lead to disease, such as neurodegeneration, developmental defects, and cancer. One area of post-transcriptional regulation that remains in its infancy of understanding is how mRNA stability is affected by other events in the mRNA life cycle, such as translation. An overarching theme has been that repression of translation initiation precedes and causes mRNA decay, but there are many contradictory examples to this generalization. Here, we focus on two systems outside this generalization. First, my lab has made a significant advance in delineating translational repression in the absence of mRNA decay during early Drosophila embryogenesis through our discovery that the post-transcriptional repressor ME31B has different regulatory impacts before and after the MZT. ME31B represses translation before the MTZT, but stimulates mRNA decay after. We have found that ME31B represses translation through an eIF4E-binding protein called Cup, which is degraded during the MZT. Thus, a critical, unresolved issue is why ME31B fails to stimulate mRNA decay before the MZT. Work from my lab and others points to a potential role for Cup in blocking mRNA decay. We will address this issue by answering two questions. 1) What is the role of Cup in embryogenesis?; 2) How is mRNA decapping generally controlled during embryogenesis? Our second area of research is understanding how translation elongation affects mRNA decay. Work in model prokaryotic and eukaryotic systems has demonstrated that codon optimality affects mRNA stability. By developing a suite of new transcriptome-wide experimental and computational tools, my lab has found that translation elongation also alters mRNA stability in humans and that these changes are mediated partially through codon usage. Here, we will answer two related questions: 3) How does translation elongation affect mRNA stability in humans?; 4) What is the role of codon optimality in controlling gene expression? To do so, we will combine genetic, genome-wide, and classical molecular biology approaches. The outcomes of our research will be an improved understanding of post-transcriptional regulation, and our insights may inform our view of how gene misregulation underlies human disease.

概括 几十年来，人们已经认识到转录后调控与转录后调控同样重要。 转录控制基因表达，但大部分转录后调控 是一个黑匣子。转录后调控的改变可能导致疾病，例如 神经退行性疾病、发育缺陷和癌症。转录后区域之一 mRNA 稳定性如何受到影响这一调控仍处于初步理解阶段 mRNA 生命周期中的其他事件，例如翻译。一个总体主题是 翻译起始的抑制先于并导致 mRNA 衰减，但是 有许多与这一概括相矛盾的例子。这里我们重点关注两个 在此概括之外的系统。首先，我的实验室在以下方面取得了重大进展： 描绘早期在没有 mRNA 衰减的情况下的翻译抑制 通过我们发现转录后阻遏物来果蝇胚胎发生 ME31B在MZT前后有不同的监管影响。 ME31B镇压 在 MTZT 之前翻译，但在 MTZT 之后刺激 mRNA 衰减。我们发现 ME31B 通过称为 Cup 的 eIF4E 结合蛋白抑制翻译，该蛋白是 MZT 期间降级。因此，一个关键的、未解决的问题是为什么 ME31B 无法 在 MZT 之前刺激 mRNA 衰减。我的实验室和其他人的工作表明 Cup 在阻止 mRNA 衰变方面的潜在作用。我们将通过回答来解决这个问题 两个问题。 1）Cup在胚胎发生中的作用是什么？ 2) mRNA如何 脱盖通常在胚胎发生过程中受控？我们的第二个研究领域是 了解翻译延伸如何影响 mRNA 衰减。在模型中工作 原核和真核系统已证明密码子最优性影响 mRNA 稳定性。通过开发一套新的全转录组实验和 计算工具，我的实验室发现翻译延伸也会改变 mRNA 人类的稳定性，这些变化部分是通过密码子的使用来介导的。 在这里，我们将回答两个相关问题：3）平移伸长率如何影响 人类 mRNA 稳定性？ 4) 密码子最优性在控制基因中的作用是什么 表达？为此，我们将结合遗传、全基因组和经典分子 生物学方法。我们的研究成果将加深对 转录后调控，我们的见解可能会告诉我们基因如何 监管不当是人类疾病的根源。