A Genetic Circuit Formed by Ribosomes

由核糖体形成的遗传回路

基本信息

批准号：
10441541
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机和不同的亚细胞室中。通常是认为这两个基本过程是未耦合的，几乎没有“串扰”。最近的证据表明异常mRNA的翻译导致遗传补偿，对快速上调具有相似功能的基因。但是，细胞质的分子机制翻译与核转录交流仍然难以捉摸。在学习翻译过程中控制氨基酸饥饿的控制，我们观察到了正在接受的基因的转录上调应力诱导的核糖体暂停。依靠新开发的测序方法以斯拉 - 赛克，我们发现了内源性核糖体足迹的存在。我们假设这些mRNA片段是新颖的染色质调节剂通过以序列依赖性方式影响基因表达。目标的目标建议是表征遗传回路偶联细胞质翻译和核转录。经过识别和映射与染色质相关的核糖体足迹，我们将阐明新型RNA类型基因表达的介导的表观遗传调节。我们提出核糖体形成的遗传回路有助于遗传鲁棒性，是压力适应的常见机制。我们还将探索设计人造核糖体足迹以实现受控基因表达的潜力，揭示了新的新疗法的途径。核糖体介导的遗传回路的概念建立是我们对分子生物学中心教条的理解的变革性，并开辟了一项新的研究探索遗传重编程的途径。