转录组水平RNA编辑的全景分析及功能研究

Human genome project (HGP) and other omics studies systematically accelerate the life science research in the past decade. In addition, the development and application of revolutionary high-throughput sequencing technologies lead life science research to an era with inexpensive production of numerous sequencing data for extensive study in the fields of genomics and transcriptomics. By using deep-sequencing technology and computational analysis, views of gene expression regulation recently have been transformed to the RNA level, and knowing that RNA regulation and its complexity may be the core for biological function regulation. RNA processing regulation, including RNA editing and alternative splicing, can produce multiple RNA products, which not only increase the protein complexity, but also enrich functional diversity, with specific spatial-temporal patterns. We propose a multi-tiered analysis of RNA editing in the whole transcriptome level as the RNA editing is critical for gene expression regulation. Specifically, we propose to deeply interrogate the RNA editing profiles in human tissues/cells by applying whole transcriptome deep-sequencing and computational analysis, and further investigate their specific traits including sequence/motif-specificity, tissue-specific regulation, and in particular, functional diversity. The knowledge we learn from the proposed study will provide insight into the more-than-expected function of RNA editing for the regulation in gene expression and tissue development.

人类基因组计划的实施、基因组和功能基因组学研究的深入均极大地推动了生命科学在整体和系统水平的发展。最新研究表明，利用新一代高通量测序和计算分析方法揭示基因表达在RNA水平的调控，对拓展有限基因的全方位功能至关重要。RNA转录加工水平相关调控（如RNA编辑、剪接等），不但可从单个基因产生参与不同生命活动调节的多种RNA和/或蛋白质，而且具有时-空特性。本申请项目在我们已建立全转录组测序和高通量计算生物学分析的系统技术基础上，以人源转录组为研究模型，通过计算分析和实验验证相结合的方法，在人转录组水平上检测RNA编辑的类型与分布，并详细研究它们的有关特征，进而深入比较分析不同人源组织细胞中RNA编辑的异同及相关功能，以期揭示RNA编辑的重要特征和组织细胞特异性等，为RNA编辑的组织发育调控作用和基因表达在RNA水平的特异性调控等前沿性研究提供基础和线索。

RNA编辑是一种通过在转录本水平改变RNA序列中特定碱基进而影响遗传信息表达的调控机制。近年来，在人基因组中鉴定出数以百万计的RNA编辑位点，探究这些RNA编辑位点的功能具有重要的生物学意义。我们开发并建立了一套全新高效、准确的RNA编辑分析流程，基于转录组数据鉴定出组织特异RNA编辑新位点，对RNA编辑簇的发生和高置信度进化保守的RNA编辑位点作用机制进行探索性研究。利用建立人胚胎干细胞定向神经细胞分化体系，研究RNA编辑酶ADAR1敲减后对人胚胎干细胞的神经发育的作用，发现ADAR1除了具有RNA编辑活性外还可以通过调节miRNA的表达进而调节了神经系统的发育。这为解析RNA编辑在神经发育、肿瘤发生和人类疾病中的功能机制提供了基础。