Computational- and experimental- driven discovery of splicing regulation and circRNA function

项目总结/摘要 细胞和生物体，从简单到复杂，都携带着组织成基因的相同遗传DNA序列。 多细胞真核生物通过一种称为替代的过程将基因转录并加工成RNA亚型 拼接选择性剪接受发育和细胞类型特异性调节。它是如何 高等生物的基因组被解码然而，关于其监管和 其产出的功能仍然没有得到答复。例如，circRNA是替代性免疫的普遍存在的产物， 剪接直到2012年才被发现，其调控和功能仍然是个谜。circRNA的发现 揭示了一个更大的关键知识差距，在该领域的“什么，如何和为什么”基因是选择性剪接。 什么样的RNA剪接变体被表达，剪接是如何被调节的，以及哪些剪接的RNA具有重要的 功能？弄清这些问题对于预测无数遗传变异中的哪一种导致疾病至关重要 以及他们这样做的原因Answers还将实现新一代数字核酸生物标志物， 疾病诊断、校正失调剪接的药物靶点和病原性 蛋白质或非编码产物（分别）以及对进化和 真核生物基因组的功能。拟议的研究将结合新的统计分析的组学数据， 采取无偏见的方法，并包括未充分研究或未注释的生物特征。 预测将与敏锐的实验验证相结合，以揭示RNA如何， 包括circRNA的剪接以及它们的功能。这项研究可能会有重大的新发现， 为什么选择性剪接存在，以及这种理解如何用于精准医学。

Project Summary/Abstract Cells and organisms, from simple to complex, carry the same genetic DNA sequence organized into genes. Multicellular eukaryotes transcribe and process genes into RNA isoforms through a process called alternative splicing. Alternative splicing is developmentally and cell-type specifically regulated. It is foundational to how higher organisms’ genomes are decoded. Yet, critical and fundamental questions regarding its regulation and the function of its output remain unanswered. For example, circRNA being a ubiquitous product of alternative splicing was only discovered in 2012, and its regulation and function remains enigmatic. circRNAs’ discovery revealed a larger critical knowledge gap in the field for “what, how and why” genes are alternatively spliced. What RNA splice variants are expressed, how splicing is regulated and which spliced RNAs have essential functions? Answering these questions is critical for predicting which of myriad genetic variants cause disease and why they do so. Answers will also enable a new generation of digital nucleic acid biomarkers and diagnostics for disease, drug targets for correcting dysregulated splicing and identification of pathogenic protein- or non-coding products (respectively) as well as fundamental basic scientific insight into evolution and function of eukaryotic genomes. The proposed research will couple novel statistical analyses of -omics data by taking an unbiased approach and including biological features that are understudied or un-annotated. Predictions will be coupled with incisive experimental validation to reveal new principles of how RNAs, including circRNAs, are spliced and how they function. This research potentiates significant new discoveries in why alternative splicing exists and how this understanding can be used for precision medicine.