RNA编辑调控的生物信息学与功能基因组学研究

RNA editing is a co-transcriptional process that introduces differences between RNA and its corresponding DNA sequence. Understanding of the RNA editing process has been broadened considerably by the next generation sequencing technology. However, fundamental issues regarding this regulatory step involving the global editome pattern, the mechanism by which its profile is maintained, as well as its evolutionary and functional outcome remain unresolved. Taking the dual-advantages of rhesus macaque as a central model animal and a species closely related to human, here we prepare to identify and decipher an accurate and informative editome in rhesus macaque that covers multiple animals, tissues, developmental stages and disease status, on the basis of our previous studies in this field. Meanwhile, we want to investigate the relevant molecular factors underlying the macaque editome detected, from the perspective of the cis- and trans-directed mechanisms associated with ADARs, as well as the stability of RNA secondary structures. Finally, on the basis of integrating the RNA editome data in human and chimpanzee and experimental validations, we prepare to study the evolutionary conservation of the editome as well as the contribution of purifying selection to editome shaping, which would provide evidence to the functional significance of this co-transcriptional regulation as a whole. The potential interactions between RNA editing process and other types of biological regulations will also be investigated in detail. In conclusion, this functional genomics study on macaque editome would provide an informative framework for further understanding of RNA editing regulations in human mechanistic and translational studies.

RNA编辑可引起基因组与其编码的转录组在特定位点的序列差异，对生命科学多领域的研究产生深远影响。新一代测序技术的出现加速了对RNA编辑调控的鉴定和理解，然而，受样本取材、数据分析等因素限制，目前对这一调控层次的整体组学模式、分子决定机制及进化与功能性认识仍处在起步阶段。本课题拟在前期工作基础上，利用恒河猴作为模式动物和人类近缘物种的双重优势，运用新一代测序技术，鉴定并分析恒河猴多个体、多组织、多发育阶段、多疾病状态下的RNA编辑组，完善对该调控层次组学模式的认识。同时，拟从ADAR 顺式与反式调控、RNA二级结构稳定性等角度，阐释上述RNA编辑组形成的分子机制。最后，拟结合人类、黑猩猩等多物种的RNA编辑组数据，并辅以分子生物学实验验证，从功能基因组学和分子演化的角度，系统研究RNA编辑调控的整体功能，探索RNA编辑与其他生物调控的关联性，为RNA编辑调控的功能研究与转化医学应用提供依据。

近年来，新一代测序技术促进了对RNA编辑调控的鉴定与理解，然而，当前对该调控层次的整体组学模式、分子决定机制及功能性认识尚处在起步阶段。本课题在前期工作基础上，首先通过开展系统的功能基因组学研究，完善了前期建立的猴“一站式”基因组知识库RhesusBase，为研究RNA编辑调控在灵长类中的特征与功能奠定了基础。基于该平台，课题组系统鉴定了恒河猴多个体、多组织、及不同病理状态的RNA编辑组，阐释了RNA编辑组形成的分子机制，并从分子演化角度证明了RNA编辑调控的整体功能性。为了进一步探究RNA编辑调控的具体生物学功能，课题在灵长类中对多个层次的调控事件进行了组学层次的研究，并通过开展功能基因组学研究，系统探究这些生物调控与RNA编辑调控的关联性，从三个角度揭示了RNA编辑调控的普遍性功能。由申请人担任通讯作者，相关工作在PNAS、Genome Biology、Molecular Biology and Evolution、PLoS Genetics等学术期刊发表SCI论文6篇。相关工作得到国际同行认可。本项目的顺利完成，为进一步深入揭示RNA编辑调控在灵长类中的生物学功能提供了基础。