VENTURE: Investigating the role of RNA structure in mRNA Export

信使核糖核酸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。以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分子的重要特征，对tRNA和rRNA的输出起着至关重要的作用。然而，RNA结构在mRNA输出中的作用尚不清楚，主要是因为在确定活细胞中mRNAs的输出相关RNA结构基序方面存在局限性。此外，突变的出口相关蛋白要么取消所有的mRNA输出，要么损害耦合的转录或翻译过程，这给剖析mRNA输出的功能带来了挑战。我们将开发几种新的方法来生成活体单分子RNA结构景观的大数据图谱，以比较核和胞质RNA。我们将开发人工智能模型来学习与出口相关的RNA结构基序。我们还将阐明RNA结构在转录过程中促进信使核糖核酸输出的新机制，并揭示信使核糖核酸输出的潜在功能重要性，如影响细胞特性。我们将利用多学科方法，从单个mRNAs到转录组水平，从支撑分子机制到表型影响，从个体调查到大数据挖掘，全面研究RNA结构在mRNA输出中的作用。这一方案产生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输出在调节细胞特性方面的潜在生物学功能将有助于我们理解这种显着的进化核质区划。新技术和新框架都有可能转化为广泛的生物体。

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.