基于信息熵的isomiR-lncRNA集成分析及在胆囊癌研究中的应用

IsomiRs, generated from miRNA locus with characteristics of sequence diversity, have been concerned as a pivotal link in non-coding RNA (ncRNA) regulatory network, and analyzing their abnormal regulatory patterns and relationships with other RNAs contribute to revealing the occurrence and development mechanism of complex diseases. On the basis of previous studies, the project aims to explore cross-talk between isomiR and lncRNA by combining theoretical research and experimental validation: ①Information entropy is used to characterize expression and function of isomiRs based on their biological characteristics. ②Relevant features are extracted, including expression, function, evolution/position, etc. In particular, target mRNAs are involved, and the correlations among different RNAs are measured by entropy. These multiple correlations are integrated by weighted entropy and further projected to interaction network. Then, the crucial RNA modules are screened based on the network. ③Instance application: crucial RNA molecules in gallbladder carcinoma are selected based on above mentioned method, and they are experimentally validated and performed functional studies. The validated results are used to further improve the analysis strategy. We aim to reveal the cross-talk between the two kinds of ncRNAs with diverged lengths in the gene regulatory network, and the relevant results will further guide to screen RNAs with tight functional relationships in diseases. This project will contribute to understanding the crucial roles of ncRNAs with complex and precise regulatory function in development of diseases.

miRNA位点产生的具序列多样性特点的isomiR是非编码RNA(ncRNA)调控的一个重要环节，解析其异常调控模式及与其它RNA的关系，有助于揭示复杂疾病的发生发展机制。基于前期研究，本课题拟结合理论研究及实验验证探讨isomiR-lncRNA的cross-talk：①基于isomiR生物学特点，利用信息熵表征其表达和功能特征；②提取isomiR与lncRNA的表达、功能、进化/位置等相关特征，特别引入靶mRNA并用熵度量RNA间关系，利用加权熵综合多种因素并投影至相互作用网络，以筛选关键分子模块；③实例应用：基于该方法筛选胆囊癌关键RNA进行实验验证及功能研究，根据反馈结果进一步完善分析策略。本课题旨在揭示这两种长度迥异的ncRNA在基因调控网络中的cross-talk，指导筛选疾病发生中功能密切相关的RNA。本研究的实施将有助于认识ncRNA复杂精确的调控功能在疾病发生中的重要作用。

曾被认为是“暗物质”的含量丰富的非编码RNA(ncRNA)在生物发育过程中发挥了重要的生物学作用，与多种疾病的发生发展密切相关，全面认识ncRNA复杂精确的调控功能有助于深入揭示基因表达调控网络的奥秘。本项目围绕ncRNA调控的一个重要环节——miRNA位点产生的具序列多样性特点的isomiR，提出基于信息熵表征isomiR并度量多种RNA间关系，围绕miRNA位点所产生的多重isomiR，基于种子区域的改变探讨可能引发的编码-非编码RNA调控网络的扰动；综合多种相关因素诠释miRNA/isomiR与lncRNA的cross-talk，以被调控的mRNA为分析媒介，构建相互作用网络并分析筛选与疾病发生发展密切相关的RNA，筛选到包括结肠癌、肺癌及前列腺癌等疾病密切相关的ceRNA调控网络，而具有表达和序列异质性的isomiR进一步复杂了多RNA间的互作模式；进而以胆囊癌为主要病种，基于筛选的胆囊癌发生过程中功能密切相关的RNA，并针对候选关键基因HP进行实验验证及功能研究，以深入揭示其在疾病发生发展中的作用，结果发现与细胞迁移和侵袭有关的HP在胆囊癌的病理生理过程中扮演着重要角色；基于非酒精性脂肪肝（NAFLD）开展的研究以Gm15622/SREBP-1c为主线，深入阐明了lncRNA Gm15622可通过海绵吸附miR-742-3p促进SREBP-1c的表达和肝脏脂质积累的分子机制，为NAFLD的防治提供了新的药物靶点；针对Notch信号通路开展的多组学数据整合分析其分子特征，特别是围绕不同RNA间的复杂互作模式探讨Notch，表明Notch信号通路与癌症发生发展密切相关，靶向Notch的治疗策略可能是精准医疗中的一个重要方向；而围绕合成致死开展的多组学相关研究，表明ncRNA在合成致死效应中也具有重要的调控作用，为从合成致死角度探讨癌症预后及治疗等提供数据参考。综合以上结果，该项目较全面地解释了miRNA/isomiR在癌症发生发展中的可能作用特征，以及从isomiR水平探讨与不同RNA间的互作模式，为系统认识ncRNA复杂精确的调控功能提供了一定的数据及方法学参考。