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A Genetic Circuit Formed by Ribosomes

由核糖体形成的遗传回路

基本信息

批准号：
10246829
负责人：
Shu-Bing Qian
金额：
$ 109.11万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2025-07-31
项目状态：
未结题

项目摘要

PROJECT SUMMARY Following transcription, mRNAs transmit the genetic information that dictates protein production. In eukaryotes, transcription and translation occur at different timings and in distinct subcellular compartments. It is commonly believed that these two fundamental processes are uncoupled and have little “cross-talk”. Recent evidence suggests that translation of aberrant mRNAs leads to genetic compensation, a transcriptional response to rapidly upregulate genes with similar functions. However, the molecular mechanisms by which cytoplasmic translation communicates with nuclear transcription remain elusive. During the course of studying translational control in response to amino acid starvation, we observed transcriptional upregulation of genes undergoing stress-induced ribosome pausing. Relying on a newly developed sequencing method, Ezra-seq, we discovered the existence of endogenous ribosome footprints. We hypothesize that these mRNA fragments serve as novel chromatin modulators by influencing gene expression in a sequence-dependent manner. The goal of this proposal is to characterize the genetic circuit coupling cytoplasmic translation and nuclear transcription. By identifying and mapping chromatin-associated ribosome footprints, we will elucidate the novel type of RNA- mediated epigenetic regulation of gene expression. We propose that the genetic circuit formed by ribosomes contributes to genetic robustness and is a common mechanism for stress adaptation. We will also explore the potential of designing artificial ribosome footprints to achieve controllable gene expression, revealing new routes toward novel therapeutics. The conceptual establishment of ribosome-mediated genetic circuit is transformative in our understanding of the central dogma in molecular biology and opens a new research avenue towards genetic reprogramming.

项目摘要转录后，mRNA传递决定蛋白质产生的遗传信息。在真核生物中，转录和翻译发生在不同的时间和不同的亚细胞区室中。人们普遍他认为这两个基本过程是分开的，几乎没有“串扰”。最近的证据表明异常mRNAs的翻译导致遗传补偿，这是一种转录反应，快速上调具有相似功能的基因。然而，细胞质中翻译与核转录的联系仍然是难以捉摸的。在学习翻译的过程中为了响应氨基酸饥饿的控制，我们观察到经历氨基酸饥饿的基因转录上调，应激诱导的核糖体停顿。依靠新开发的测序方法Ezra-seq，我们发现内源性核糖体足迹的存在。我们假设这些mRNA片段作为新的染色质调节剂通过以序列依赖性方式影响基因表达。这个目标建议是表征耦合细胞质翻译和核转录的遗传电路。通过识别和绘制染色质相关的核糖体足迹，我们将阐明新类型的RNA- 介导的基因表达的表观遗传调控。我们认为核糖体形成的遗传回路有助于遗传鲁棒性，并且是压力适应的常见机制。我们亦会探讨设计人工核糖体足迹以实现可控基因表达的潜力，揭示了新的新疗法的路线。核糖体介导的遗传回路的概念建立是在我们对分子生物学中心法则的理解中具有革命性意义，并开启了一项新的研究。基因重组的途径。