重大疾病基因组与表观组改变驱动的非编码RNA(miRNA/lncRNA)调控机制及其功能研究

Non-coding RNAs (ncRNAs), with its diverse functions, involve in extensive key biological processes. Exploration of complex regulatory mechanisms in organisms for non-coding RNAs becomes a new challenging topic. A large number of enomic/epigenomic changes play important driver roles in major diseases, especially cancer. Thus, recognizing and analyzing dysfunctional non-coding RNAs induced by genomic/epigenomic alterations will become an important way to understand the complex regulatory mechanism underlying cancer. In this work, we integrate genomic and epigenomic omics data detected using the next generation sequencing and microarray techniques, and identify non-coding RNAs drove by alterations in genome and epigenome. Furthermore, these genomic/epigenomic alteration-induced dysfunctional ncRNAs are explored from multiple levels by integrating multiple omics data. Through building cancer-specific ncRNA-associated competitive regulation networks, we mine cancer-related competitive triple modules and identify the key genomic/epigenomic alteration-induced ncRNAs. Finally, an integrative bioinformatics platform for identification of human cancer-related genomic/epigenomic alteration-induced ncRNAs, characterization of corresponding regulatory networks, identification of competitive triple modules and functional analysis is developed, which can provide the important basis for ncRNA-based cancer diagnosis and treatment.

非编码RNA（lncRNA、miRNA）凭借其功能的多样性参与许多生物学功能，探索非编码RNA在生物体内复杂调控机制是具有挑战意义的课题。基因组上发生的大量遗传改变以及表观遗传层面上的大量失调是造成重大疾病，尤其癌症发生发展的重要驱动因素。识别和解析癌症中基因组与表观组改变驱动的非编码RNA将会成为破解癌症发生发展过程中复杂调控机制的重要手段。本课题从基因组和表观组出发，利用新一代测序和芯片等高通量技术所检测的组学信息，识别癌症中基因组与表观组改变驱动的非编码RNA，从多层面探索癌症中起驱动作用的非编码 RNA，进而构建癌症特异非编码RNA内源竞争性调控网络，挖掘驱动癌症发生的非编码RNA竞争三元组模块以及关键节点，建立集人类癌症非编码RNA拷贝数变异和表观失调识别、调控网络刻画、竞争三元组模块识别以及功能分析于一体的综合生物信息学平台，为实现非编码RNA在癌症中的诊断与治疗奠定重要基础。

本项目按原计划完成。在项目实施过程中，我们融合基因组与表观组学信息，系统解析重大疾病中非编码RNA的调控机制。识别基因组变异对ceRNA调控关系的扰动影响，建立LnCeVar数据平台；解析恶性肿瘤DNA甲基化介导的转录调控模式；在人类癌症中识别功能驱动lncRNA，及其驱动转录影响的子通路，并解析重大疾病免疫相关lncRNA功能分子；解析泛癌lncRNA-lncRNA免疫共调控机制。并扩展了我们的研究工作：建立了单细胞水平LncRNA相关ceRNA调控机制预测与分析平台；在非小细胞肺癌中识别了免疫治疗相关DNA甲基化标记的功能；识别和表征与药物敏感性相关的lncRNA-TF-gene调控三元组；基于选择性剪接和RNA结合蛋白的调控解析癌症机制；建立lncRNA编码的功能肽的数据资源TransLnc。研究成果发表在《Nucleic Acids Research》、《Nature Communications》、《Cancer Research》等杂志上，发表SCI论文26篇；培养生物信息学专业研究生20名；研究成果为重大疾病的机制解析提供新的思路，为疾病的诊断和治疗提供了理论依据，具有潜在的社会效益和经济价值。