Exploring the connections between translation and mRNA decay

探索翻译和 mRNA 衰变之间的联系

• 批准号: 10468440
• 负责人: Olivia Selfridge Rissland
• 金额: $ 2.22万
• 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/10468440
• 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.

总结 几十年来人们已经认识到，转录后调控与 转录控制基因表达，但大部分的转录后调节 是一个黑匣子。转录后调节的改变可导致疾病，例如 神经退化、发育缺陷和癌症。转录后的一个区域 对mRNA的稳定性如何影响调控的理解仍处于起步阶段 mRNA生命周期中的其他事件，例如翻译。一个重要的主题是 翻译起始的抑制先于并导致mRNA的衰变，但 有许多与这一概括相矛盾的例子。在这里，我们关注两个 系统之外的一般化。首先，我的实验室在 描述在没有mRNA衰变的情况下， 果蝇胚胎发生通过我们的发现， ME31B在MZT之前和之后具有不同的监管影响。ME31B抑制 翻译之前MTZT，但刺激mRNA衰变后。我们发现 ME31B通过一种称为Cup的eIF4E结合蛋白抑制翻译， 在MZT期间降解。因此，一个关键的，未解决的问题是为什么ME31B未能 在MZT之前刺激mRNA衰变。我的实验室和其他人的工作表明， Cup在阻断mRNA衰变中的潜在作用。我们将通过回答以下问题来解决这个问题： 两个问题。1)Cup在胚胎发生中的作用是什么？2)mRNA如何 在胚胎发生过程中一般控制去盖？我们的第二个研究领域是 理解翻译延伸如何影响mRNA衰变。模型中的工作 原核和真核系统已经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 利用计算机工具，我的实验室发现翻译延伸也会改变mRNA 这些变化部分通过密码子使用介导。 在这里，我们将回答两个相关的问题：3）翻译延伸如何影响 人类的mRNA稳定性？4)密码子最优性在控制基因中的作用是什么 表情？为此，我们将联合收割机结合遗传的、全基因组的和经典的分子生物学技术， 生物学方法。我们研究的结果将是对以下问题的更好理解： 转录后调控，我们的见解可能会告知我们的看法，基因如何 失调是人类疾病的基础。