表观遗传调控基因表达系统的建模与分析

Gene expression systems are central to the study of molecular systems biology; epigenetic has an important impact on gene expression, involves the regulation of many molecules and takes part in a variety of physiological and pathological processes. For the limitations of past epigenetic systems and gene expression systems studied separately, the project intends to combine the experimental data and evidences to construct a comprehensive, two different time-scale model which takes both upstream epigenetic and downstream gene expression system kinetics into account, and then we simulate and analyze the model system. We will focus on how various histone modifications in the upstream(such as histone methylation, acetylation, etc.) affect gene expression dynamics in the downstream (including transcriptional burst kinetics, temporary and static distributions of gene products, system energy landscape functions, the first passage time, etc.) and the effect of enhancer’s regulation on gene expression levels. Through systematic research, we try to find out the essential mechanism of upstream epigenetic dynamics affecting downstream gene expression kinetics. Relevant studies have important theoretical and practical values for understanding the mechanism of disease caused by the mutations in various epigenetic regulatory factors, and lay a solid theoretical foundation for the future diagnosis and treatment of diseases as well as the research and development of new drugs by epigenetic.

基因表达系统是分子系统生物学的研究核心，而表观遗传对基因表达有重要影响且其本身会涉及众多分子的调控并参与各种生理和病理过程。针对过去表观遗传系统和基因表达系统被分开研究的局限，本项目拟结合实验数据或证据，构建同时考虑上游表观遗传动力学与下游基因表达动力学两种不同时间尺度的综合模型，并对模型系统进行仿真和分析。将重点研究上游各种组蛋白修饰作用（如组蛋白甲基化、乙酰化等）如何影响下游的基因表达动力学（包括转录爆发动力学，基因产物的动态和静态分布，系统能量景观函数，首次穿越时间等）及增强子调控对基因表达水平的影响。通过系统研究，试图找出上游表观遗传动力学影响下游基因表达动力学的本质机制。相关研究对因表观遗传的各种调控因子突变而导致疾病的机理理解具有重要的理论意义与实际价值，并为以后利用表观遗传开展疾病诊断与治疗以及有关新药研发等奠定坚实的理论基础。

表观遗传与基因调控息息相关，而表观遗传本身又涉及到众多分子的调控，对许多生理和病理过程有重要影响，并参与决定基因表达及细胞功能、形态。eRNA是增强子转录而成的一种非编码RNA，作为一种重要的表观遗传因子，其如何调控基因表达目前尚不明确。我们通过构建单基因表达调控的随机动力学模型，并进行理论分析和数值模拟以及结合实验数据来得出结论。我们发现基因能够利用环路长度来调节mRNA的表型，同时能够以直接提升基因产物mRNA生成速率的方式达到最高的mRNA均值和最低的mRNA噪声，并在此基础上进一步推广，调查其他表观遗传因子调控基因表达的一般规律。我们的结论阐明了eRNA这种非编码RNA在分子水平调控基因表达的内在机制，也为研究其他表观遗传因子如何调控基因表达提供了研究思路，并为后续进一步研究表观遗传影响细胞生长发育以及疾病的诊断与治疗奠定了坚实的理论基础。