融合基因组变异和表观改变重建泛癌关键增强子图谱及其功能分析

There are a large number of altered cis-regulatory elements in human cancer genome. They play critical roles in the occurrence and development of cancer by influencing gene expression. Most of studies on cis-regulatory elements are limited to gene promoter. However, there is few research on molecular mechanisms of other regulatory elements such as enhancers during carcinogenesis. Systematically identitying key enhancers in human cancers and studying its biological functions and molecular mechanisms is an important scientific research. In this work, we proposed an integrated optimizing strategy to systematically identify cancer-related key enhancers through the fusion of multi-omics data derived from next-generation sequencing technology, such as genome, epigenome and transcriptome data. Subsequently, we re-constructed pan-cancer atlas of cancer-related key enhancers. From genomic level to epigeneitc level, the atlas systematically showed a landscape of cancer-reated key enhancers across 12 human cancer types and visualized enhancer-related alterations of multi-omics. We profoundly dissected enhancer-mediated molecular mechanisms of tumorigenesis, and identified potential enhancer prognostic biomarkers. Finally, an integrative bioinformatic platform for identication of cancer-related key enhancers, re-construction of pan-cancer atlas of key enhancers and functional analysis is developed. Our results will help to systematically understand the functions of enhancers and comprehensively reveal how enhancers involved in the pathogenesis of cancer, and provide new opportunities for novel drug targets, cancer diagnosis and treatment.

人类癌症基因组中存在大量异常的非编码调控元件，通过干扰基因转录调控进而导致癌症的发生。癌症非编码调控元件的研究大多局限于基因的启动子，而对于其他重要的非编码调控元件增强子的致癌分子机制研究甚少。因此，识别癌症关键增强子调控元件及其功能研究是一个重要的科研课题。本研究从基因组到表观组，采用信息学算法刻画多组学失调信息流动，识别癌症关键增强子元件，进一步重建泛癌关键增强子图谱，可视化增强子的癌症多组学失调信息，解析增强子元件介导的致癌分子机制，识别癌症关键增强子预后标志物，开发泛癌关键增强子的识别与功能分析平台。为深入剖析异常增强子驱动的癌症分子机理与人类癌症发生发展相关的增强子标志物及干预靶点的识别提供了重要的科学依据，具有潜在的社会价值和经济效益。

本项目按原计划完成。癌症的发生风险与基因组遗传变异密切相关，研究显示癌症基因组中落入非编码区域的遗传变异远比落入蛋白编码区域的遗传变异多很多。癌症基因组非编码区域的功能解析是当前生命科学领域的前沿热点课题。因此，本研究从整合癌症多组学数据出发，以人类癌症（如乳腺癌和肺癌）为疾病模型，基于新一代测序数据识别增强子元件集合，构建癌症背景下特异的调控网络，进一步融合基因组、表观组与转录组学的失调信息，系统地识别癌症关键增强子，重建人类癌症关键增强子图谱，系统地从基因组层面到表观组层面，展示人类癌症失调增强子的全貌，直观地可视化癌症关键增强子的癌症多组学失调信息，深入系统地开展癌症关键增强子功能研究，解析以增强子的多层面异常为基础的人类癌症的发病机制，识别癌症关键增强子预后标志物。我们还进一步扩展了本研究工作，基于完善的人类癌症相关的多组学数据资源，以肺腺癌为疾病模型，通过整合癌症基因组遗传改变和非编码RNA转录组学数据，构建了肺腺癌背景下长链非编码RNA（lncRNA）的拷贝数改变图谱，识别了肺腺癌预后相关的拷贝数改变驱动的lncRNA标志物；另一方面，通过整合表观遗传组学和调控组学数据，构建了癌症相关的染色质状态修饰的TF-Gene调控网络，刻画了表观遗传改变与网络基序的协同调控作用，挖掘染色质状态修饰的癌症特异关键预后标志物。此外，为了促进解析lncRNAs参与癌症发生发展的调控机制研究，我们开发了癌症关联的功能性lncRNA-靶基因调控综合性数据平台，用于查询与刻画癌症风险lncRNA介导的调控机制、关键下游靶基因、风险lncRNA-靶基因调控的生物学功能和动态性改变。本项目共发表SCI论文4篇，研究论文发表在国外著名生命科学杂志《Nucleic Acids Research》、《Oncogene》、《Molecular Therapy-Nucleic Acids》和《International Journal of Cancer》杂志上。本研究所取得的研究成果为深入剖析非编码调控元件增强子和非编码RNA驱动的癌症发生的分子机理研究提供了重要的科学依据，为人类癌症的临床诊断、癌症精准医疗和癌症用药奠定了理论基础，具有潜在的经济效益和应用价值。