两类环形RNA的生成加工机制研究及其功能探索

项目名称： 两类环形RNA的生成加工机制研究及其功能探索

项目编号： No.91440202

项目类型： 重大研究计划

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 陈玲玲

作者单位： 中国科学院上海生命科学研究院

项目金额： 300万元

中文摘要： 近十年来在生物体内发现了大量与mRNA结构类似，却不具备编码功能蛋白质能力的长链非编码RNA。利用新的富集手段结合高通量分析，最近我们报导了人体内存在上万条具有特殊结构的长非编码RNAs，其中多数为环形RNAs（circular RNAs）。环形RNAs不具有5'末端帽子和3'末端poly(A)尾巴，以共价键成环，并具有潜在的生物学功能。根据其产生机制不同，分为外显子来源和内含子来源的环形RNAs。我们研究证明RNA序列互补对外显子环形RNAs的产生和可变环化调控至关重要；而内含子环形RNAs的生成则依赖于一些关键核酸序列。本项目旨在前期研究基础之上，揭示环形RNAs生成转录和剪接的协调互作、阐明两类环形RNAs的加工成熟机制、探索环形RNAs调控基因表达的功能。获得成果将为深入认识环形RNAs的生成加工代谢及生物学功能提供坚实的分子基础和理论依据，有望在本领域继续保持国际领先的研究进展。

中文关键词： 环形RNA；外显子环化；内含子环化；可变环化；基因表达调控

英文摘要： While most annotated long noncoding RNAs (lncRNAs) appear indistinguishable from mRNAs, having 5'cap structures and 3'poly(A) tails, recent work has revealed new formats. Such lncRNAs are processed and stabilized by other mechanisms, such as capped by snoRNP complexes at both ends or by forming circular structures. Importantly, these lncRNAs have also been implicated in gene expression regulation in mammalian cells. In fact, the majority of these lncRNAs with new formats are circular RNAs. With the non-poly(A) selection and RNase R enrichment, we and others have very recently reported ten thousands of circular RNAs from many loci in mammals. Circular RNAs can be produced from back splice circularization of exons (exon circularization) or from excised introns owing to a failure in debranching (circular intronic RNAs, ciRNAs). We have demonstrated that exon circularization is dependent on RNA pairing formed by complementary sequences across flanking introns. Importantly, the competition of RNA pairing formation across flanking introns or within individual introns significantly affects exon circularization and leads to alternative circularization, resulting in multiple circular RNA transcripts produced from a single gene. On the other hand, the processing of ciRNAs depends on a consensus motif near the 5'splice site and the branchpoint site. In addition, some ciRNAs largely accumulate to their sites of transcription and boost the transcription of their parent genes. Together, our findings greatly extend the complexity of mammalian co-/post-transcriptional regulation.. However, the biogenesis and function of these two classes of circular RNAs have largely remained elusive. This proposal is aiming to further decipher the detailed processing mechanisms of these circular RNAs, including the coordination of exon/intron circularization with transcription and splicing regulation, the identification of key cis-elements and trans-factors involved in different types of RNA circularization, and the functional implications of circular RNAs in gene regulation. Taken together, our study will lead to a better understanding of circular RNA biogenesis and provide new insights into the mechanistic basis for their functional implications.

英文关键词： circular RNA;exon circularization;intron circularization;alternative circularization;gene expression regulation