融合多组学数据优化筛选恶性肿瘤中表观失调非编码RNA及其功能研究

The development of human cancer is driven by changes in the genetic and epigenetic landscape of the cell. However, identification and functional analysis of epigenetically dysregulated noncoding RNAs (ncRNAs) and integration of different types of genomic datasets to discover the regulatory networks mediated by ncRNAs are challenging. This application describes the development of computational methods and integrative genomic strategies for systematically dissecting the the epigenetically dysregulated ncRNA in cancer, and a combination of computational and experimental approaches to unravel several important functional networks mediated by ncRNA in multiple types of cancer. Specifically, it will (i) develop a computational method to interrogate ncRNA methylation, histone modification and expression in tumor and normal samples and utilize an integrative genomic strategy to identify epigenetically dysregualted ncRNAs, (ii) identify the transcriptional and post-transcriptional regulatory networks mediated by ncRNAs and summarize the regulatory principles of known cancer related ncRNAs, and integration of the principles to discover the ncRNA biomarkers for the diagnosis, treatment and prognosis of human cancer, (iii) predict the functions of ncRNAs based on the regulatory targets and validate the function of ncRNAs and the regulatory relationship using experimental approaches. In addition to its scientific proposal, this application develops cutting-edge computational methods, and uses a combination of computational and experimental approaches to understand the upstream mechanism of ncRNAs expression dysregulation and the downstream regulatory networks mediated by ncRNAs in cancer. The results obtained by this application will be a highly valuable resource for investigations at understanding epigenetic regulation of cancer and identification of epigenetic-based therapeutic targets.

恶性肿瘤的发生发展是遗传与表观遗传共同驱动的结果。系统鉴定识别恶性肿瘤发生发展过程中表观失调的非编码RNA (noncoding RNA, ncRNA)并探讨其介导的调控网络在恶性肿瘤中的作用机制是具有挑战意义的课题。本课题将以恶性肿瘤中ncRNA不同层面的组学资源为起点，开发计算学方法鉴定恶性肿瘤发生发展过程中表观失调的ncRNA，进一步构建表观失调ncRNA介导的转录和转录后调控网络，归纳总结已知恶性肿瘤相关ncRNA的拓扑结构以及调控规律，开发恶性肿瘤相关ncRNA诊断、预后标记优先化方法，进一步基于表观失调ncRNA介导的转录和转录后失调靶基因预测ncRNA生物标记的分子功能，最后利用分子生物学实验证实表观失调ncRNA的调控作用以及分子功能，形成以ncRNA为核心的复杂分析系统，建立查询、计算及分析的一体化平台，为恶性肿瘤及其进展发病机制的理解提供新的视角和新的思路。

本项目按原计划完成。在本项目中，通过整合恶性肿瘤中的基因组、转录组、表观组和功能数据，我们开发了计算学方法识别了恶性肿瘤及其进展过程中表观失调的ncRNA，探究了不同肿瘤亚型中ncRNA失调模式的异同。进一步开发了LncMod、FACER以及MERIT等计算学方法系统识别了恶性肿瘤及其进展过程中ncRNA介导的转录及转录后调控失调关系，构建了多种恶性肿瘤中ncRNA多层次功能调控网络。通过网络结构分析，我们识别了恶性肿瘤中保守的泛癌lncRNA调控子、中度调控子以及癌症特异的lncRNA调控子，功能分析揭示了泛癌的调控子具有更低的组织特异性表达模式、具有更高的保守性并且和恶性肿瘤的发生发展密切相关。通过lncRNA调控子介导的调控扰动分析，我们预测并用低通量实验证实了调控子的分子功能。特别地，我们还拓展了本项目的研究工作，系统地分析了恶性肿瘤中遗传变异对于ncRNA以及RNA结合蛋白调控网络的影响。此外，我们系统分析了恶性肿瘤进展过程中lncRNA转录组的动态改变，识别了肿瘤进展相关的lncRNA分子标记，并结合转录调控数据分析了潜在的上游调控因子。在研究分析的同时，我们也归纳总结了恶性肿瘤中ncRNA调控以及协同调控的规律，受多个杂志社的邀请撰写了恶性肿瘤中ncRNA调控相关的多篇综述性文章。为了进一步推广本项目的研究成果，我们开发了多个R程序软件包以及LncMAP等多个在线数据分析平台，为恶性肿瘤中ncRNA研究及其分子机制的探究提供了新的视角。在本项目的支持下，已经发表SCI论文15篇，主要刊发于国外著名生命科学相关杂志《Hepatology》、《Nucleic Acids Research》、《Briefings in Bioinformatics》及《Molecular Therapy: Nucleic Acids》等。

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