解析人类癌症风险非编码RNA（miRNA/lncRNA）协同调控网络及其功能分析

Non-coding RNAs (ncRNAs) with widespread transcription and complex regulatory mechanisms require us to redefine the mechanistic insights into the RNA world. Exploration of the regulatory functions of ncRNAs has become the key to understanding the complicated molecular mechanisms underlying human cancer. However, how ncRNAs cooperatively function to induce aberrant functions in cancer is still unknown. In this work, we integrate multi-omics data derived from next-generation sequencing technology, such as genome, epigenome, transcriptome and regulatome data, to analyze ncRNAs (microRNAs and long noncoding RNAs) that are associated with genetic information transfer. From the perspective of systems biology, cancer-related ncRNAs are systematically identified through the fusion of a variety of biological resources and the application of different optimization strategies. Subsequently, we construct and analyze ncRNA-mediated cooperative regulatory networks, and then identified key ncRNA drivers and their associated cooperative modules. Furthermore, the biological pathways of these key ncRNAs are determined. Finally, an integrative bioinformatic platform for identification of cancer-related ncRNAs, characterization of ncRNA-mediated cooperative networks and functional analysis is developed. Our results will help to systematically understand the functions of ncRNAs and comprehensively reveal how ncRNAs involved in the pathogenesis of cancer, and provide new opportunities for cancer diagnosis and treatment.

非编码RNA凭借广泛的转录及复杂的调控机制颠覆了RNA世界的格局，俨然已成为剖析人类癌症发病机理的关键突破口。然而，对非编码RNA是如何协同调控进而诱导癌症相关功能的异常所知甚少。本课题以遗传信息传递相关的非编码RNA（miRNA与lncRNA）为核心，从系统生物学角度，通过集成与分析新一代测序技术产生的多组学数据（如基因组、表观组、转录组与调控组），基于融合生物学资源与优化策略，全面地识别人类癌症非编码RNA，构建与解析人类癌症非编码RNA参与的协同调控网络，挖掘关键的非编码RNA驱动子及其协同模块，探索非编码RNA参与的生物学通路，并建立人类癌症非编码RNA识别、协同网络刻画以及功能分析于一体的复合型生物信息学平台，为系统地理解非编码RNA功能提供关键的信息，为全面地揭示非编码RNA在癌症中的作用机制奠定坚实的基础，更为实现从非编码RNA角度诊断与治疗癌症提供新的契机。

越来越多的证据表明蛋白质编码基因的变异并不能完全解释癌症的发生发展进程，非编码RNA由于其转录广泛性及调控机制复杂性已然成为解析癌症发展机理的关键突破口。然而，以非编码RNA为核心的癌症发生发展机理相关协同调控及功能解析研究仍处于初级阶段。本项目以非编码RNA（miRNA与lncRNA）为核心，基于整合的人类癌症多组学数据（如基因组、表观组、转录组与调控组），开发新颖算法与优化资源策略，通过协同多种非编码调控机制于泛癌中系统识别癌症关键驱动非编码RNA及其参与的Hallmark关联互斥模块，解析其潜在的功能机制和临床预后关联，并基于大规模基因扰动互作资源，全面解析非编码RNA功能性；进一步，基于绘制的非编码RNA变异图谱，挖掘胶质瘤中失调的竞争性内源RNA网络，揭示其生物学功能及其与临床组织学亚型的高度相关性，与此同时，系统识别预测乳腺癌患者复发风险的lncRNA signature并明确其独立于临床组织病理学因素预后效能；此外，为进一步拓展本项目研究，搭建于单细胞水平下解析癌细胞功能状态的分析平台CanserSEA，建立人类疾病相关增强子全面蓝图资源平台DiseaseEnhancer，构建lncRNA-染色质互作图谱资源平台LnChrom，并基于lncRNA-染色质互作整合分析结合表观遗传图谱和调控元件信息以阐明lncRNA功能依赖于不同调控元件的调控。项目所开展的系列研究工作，为整合识别人类癌症风险非编码RNA及系统解析非编码RNA的功能提供关键信息，为全面揭示非编码RNA在癌症进程中的功能机制及实现于非编码RNA视角开展的临床诊疗策略提供坚实支撑。