心血管发育与疾病中非编码RNA的表观遗传调控机制及其功能研究

Recent studies revealed that the human genome encodes thousands of noncoding RNAs (ncRNAs) with little protein-coding capacity. NcRNAs were shown to play important roles in cardiovascular development and are potentially a new class of therapeutic targets for cardiovascular diseases. With the development of genomic technologies, especially those based on next generation sequencing, bioinformatic analyses provide unparalleled opportunities to characterize the functional networks of ncRNA in cardiovascular development and related disease. However, analysis and integration of different types of genomic datasets to generate testable hypotheses is challenging, and systematic approaches to characterize ncRNA function in cardiovascular development and related diseases are lacking. This application describes the development of computational methods and integrative genomic strategies for systematically dissecting the epigenetic regulation of ncRNA in cardiovascular development and related diseases, and a combination of computational and experimental approaches to unravel several important functional networks of ncRNA. Specifically, it will (i) develop computational methods for repurposing the publically available omics data to interrogate ncRNA methylation, histone modification and expression and utilize an integrative genomic strategy to investigate the epigenetic regulation of ncRNAs that may be important for cardiovascular development and diseases, (ii) analyze the individual or synergetic epigenetically regulatory patterns of ncRNA in the context of cardiovascular development and diseases, summarized the principle of ncRNA regulation and integration of the principle to optimal screening of epigenetically dysregulated ncRNA biomarkers in cardiovascular diseases, (iii) construct the multiple types of regulatory networks mediated by ncRNAs, mainly from the levels of epigenetic regulation, transcriptional regulation, ceRNA interaction networks and the ncRNA/TF synergetic regulation network, and predict the functions of ncRNAs based on the multiple regulatory networks of ncRNAs and finally validate the regulatory relationships and predicted function using experimental approaches. In addition to its scientific proposal, this application proposes a comprehensive programs and web platforms for investigators in the fields of computational genomics, ncRNA and cardiovascular development and diseases, as well as develops cutting-edge computational methods, and uses a combination of computational and experimental approaches to understand the function of ncRNA in cardiovascular development and diseases. Together, these results will not only improve our understanding of the mechanisms underlying cardiovascular development and diseases, potentially providing new epigenetic-based therapeutic targets for prevention, earlier diagnostics and improved therapeutics, but also provide a more robust framework for future ncRNA studies in any disease context.

心血管发育和疾病发生发展与ncRNA密切相关，剖析其在心血管系统中的表观调控机制及功能具有挑战意义，计算系统生物学研究策略为该领域注入新的血液。本课题通过整合DNA甲基化组、组蛋白修饰组等高通量生物图谱完善ncRNA信息；分析发育和疾病中ncRNA的表观调控模式及表观调控的协同性，建立风险标记的预测评价模型，识别疾病中关键的ncRNA；创新地构建ncRNA介导的多样式调控网络实现ncRNA功能的系统识别：主要涉及表观调控、转录调控、竞争调控及协同调控网络。本课题旨在实现挖掘心血管发育和疾病中关键的ncRNA，ncRNA表观调控机制及重要生物学功能的剖析，建立ncRNA标记及其介导的复合调控模块识别的生物信息学分析平台，应用于心衰、房颤、高血压等疾病数据，剖析疾病特异的ncRNA表观调控模式及实现基于调控模块的功能预测，推进多ncRNA多基因研究、探讨心血管系统的正常生理和病理有重大意义。

心血管发育和疾病发生发展与ncRNA密切相关，剖析其在心血管系统中的表观调控机制及功能具有挑战意义，计算生物学研究策略为该领域注入新的血液。历经4年时间，本项目实现和完善基于高通量测序技术和多源特征信息融合技术的ncRNA计算识别与挖掘方法；建立预测评价模型和算法，识别心血管发育和相关疾病中表观修饰动态或异常变化的ncRNA；实现ncRNA介导的多样式调控网络的构建方法，构建出稳定且覆盖度较高的ncRNA介导的多样式调控网络，获得ncRNA及其形成的复合模块作为心血管疾病的诊断和预后标记；结合多样式调控模式实现ncRNA调控生物学功能识别，并结合生物学实验进行证实，阐明心血管发育和疾病中表观改变的ncRNA影响的生物学通路；开发面向用户简单易用且可移植性强的ncRNA表观调控机制分析及多角度预测ncRNA功能的生物信息学平台。另外，我们拓展了本研究工作，开发整合基因组、表观基因组以及转录调控组信息的增强子lincRNA识别方法；并利用心肌分化过程中表观遗传调控数据构建增强子组合调控动态图谱，揭示心肌发育相关的重要增强子调控；拓展分析了疾病突变导致的miRNA/lncRNA/circRNA获得性调控的现有的计算和实验方法，提出整合计算和实验技术的框架来研究复杂疾病中获得性功能突变对miRNA/lncRNA/circRNA结合的扰动及信号通路功能的影响。本项目发表研究论文18篇，SCI收录18篇；获黑龙江省高校科学技术一等奖；一些核心方法被编写成软件包或将主要结果搭建成在线免费可用的数据资源，包括心血管疾病ncRNA数据库cardio-ncRNA、心血管组织富集lncRNA平台CARDIO-LNC、优化筛选表观调控子FACER、lncRNA介导转录失调的软件与平台LncMAP。参加国际和国内学术会议专题报告或研讨会45人次。协助培养生物信息学专业研究生3名，博士研究生5名。在本课题基础上，负责人成为黑龙省生物医学工程学科后备带头人并获资助，获国家自然科学基金和黑龙江省杰出青年基金，编写“十三五“全国高等医学院校本科规划教材和研究生教材各1部，以第二主编编写英文专著1部及其他中英文专著3部。本项目的完成为心血管系统发育和疾病发生发展过程中ncRNA的系统生物医学研究提供坚实的理论基础，将推动对ncRNA在心血管系统发育和疾病发生以及进展过程中的认识。