VENTURE: Investigating the role of RNA structure in mRNA Export

mRNA输出是基因表达的关键步骤，与转录和转录后过程密切相关。先前的研究已经定义了许多出口相关蛋白。即使使用相同的蛋白质，单个mrna也可以具有不同的输出速率，但速率控制机制尚不清楚。RNA结构作为RNA分子的一个重要特征，对tRNA和rRNA具有重要的输出作用。然而，RNA结构在mRNA输出中的作用尚不清楚，这主要是由于在确定活细胞中mRNA输出相关的RNA结构基序方面存在局限性。此外，突变的输出相关蛋白会破坏所有mRNA的输出并破坏偶联转录或翻译过程，这对解剖mRNA输出的功能提出了挑战。我们将开发几种新方法来生成体内单分子RNA结构景观的大数据图谱，以比较核RNA和细胞质RNA。我们将开发人工智能模型来学习输出相关的RNA结构基序。我们还将阐明RNA结构在转录过程中促进mRNA输出的作用的新的机制见解，并揭示mRNA输出的基础功能重要性，例如影响细胞身份。我们将利用多学科方法全面研究RNA结构在mRNA输出中的作用，从单个mRNA到转录组水平，从基础分子机制到表型影响，从个体调查到大数据挖掘。从这个项目中获得的知识和技术进步将彻底改变我们目前的理解和研究方法。在我们的工作中，mRNA输出在调节细胞身份方面的潜在生物学功能将有助于我们对这种显著的进化核-细胞质区隔化的理解。新技术和新框架都有可能转化为广泛的生物。

mRNA export is a key step in gene expression, tightly linked with both transcriptional and post-transcriptional processes. Previous studies have defined many export-associated proteins. Individual mRNAs can have distinct export rates even using the same proteins, but the rate-controlling mechanisms are unknown. RNA structure, as an important feature of RNA molecules, plays an essential exportrole for tRNA and rRNA. However, the role of RNA structure in mRNA export is unknown, mainly due to limitations in determining export-associated RNA structure motifs for mRNAs in living cells. Furthermore, mutating export-associated proteins that either abolish all mRNA export and impair the coupled transcription or translation processes, pose challenges for dissecting the function of mRNA export. We will develop several novel methods to generate a Big Data atlas of in vivo single-molecular RNA structure landscapes to compare nuclear and cytosolic RNAs. We will develop AI models to learn export-associated RNA structure motifs. We will also elucidate novel mechanistic insights into the role of RNA structure during transcription for facilitating mRNA export and uncover the underpinning functional importance of mRNA export, such as influencing cell identity. We will harness multidisciplinary methods to comprehensively investigate the role of RNA structure in mRNA export, from single mRNAs to the transcriptome level, from underpinning molecular mechanisms to phenotypic impacts, from individual investigation to Big Data mining. Both knowledge and technology advances derived from this programme will revolutionarily transform our current understanding and research approaches. The potential biological function of mRNA export in regulating cell identity in our work will shed light on our understanding of this remarkable evolutionary nucleus-cytoplasm compartmentalization. Both novel technologies and new frameworks will have the potential for translation to a broad range of organisms.