Exploring the connections between translation and mRNA decay

摘要 几十年来，人们已经认识到转录后调控与 转录用于控制基因表达，但大部分是转录后调节 是一个黑匣子。转录后调控的改变可能导致疾病，例如 神经退化、发育缺陷和癌症。转录后的一个领域 目前尚处于理解阶段的调控是如何影响mrna稳定性的。 由信使核糖核酸生命周期中的其他事件，如翻译。一个重要的主题是 对翻译启动的抑制先于并导致了信使核糖核酸的衰退，但是 对于这种概括，有许多相互矛盾的例子。在这里，我们重点关注两个 不属于这一概括的系统。首先，我的实验室在以下方面取得了重大进展 在早期没有mRNA衰退的情况下描述翻译抑制 通过我们发现的果蝇胚胎发生的转录后抑制因子 ME31B在MZT前后有不同的调节作用。ME31B压制 翻译前的MTZT，但刺激后的mRNA衰变。我们发现， ME31B通过一种名为CUP的eIF4E结合蛋白抑制翻译，该蛋白是 在MZT期间降解。因此，一个关键的、悬而未决的问题是为什么ME31B未能 在MZT前刺激mRNA的衰退。我的实验室和其他人的研究表明 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在胚胎发育中的作用是什么？2)mRNA是怎样的？ 在胚胎发育过程中，去顶通常受到控制？我们的第二个研究领域是 了解翻译延长如何影响信使核糖核酸的衰变。在模型中工作 原核和真核系统已经证明密码子的优化性影响 信使核糖核酸稳定性。通过开发一套新的转录组范围的实验和 计算工具，我的实验室发现翻译延长也会改变mRNA 这些变化部分是通过密码子的使用来调节的。 在这里，我们将回答两个相关的问题：3)翻译延伸率是如何影响的 人类信使核糖核酸的稳定性；4)密码子最佳性在控制基因中的作用是什么？ 表情？要做到这一点，我们将结合遗传、基因组和经典分子 生物学走近了。我们研究的结果将是更好地理解 转录后调控，我们的洞察力可能会告诉我们基因是如何 监管不善是人类疾病的根源。

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.