多目标约束下DNA甲基化动态模式的建模与分析

ERK/MAPK signal transduction networks transmit and integrate the intracellular and extracellular information, and induce random fluctuations in the intracellular ETS1 protein level, thus making the DNA methylation pattern dynamic change. It is an important biological issue to quantify the interactive effect of DNA methylation and environmental noise and elucidate the biological functions of DNA methylation pattern. According to recent experiment and related data, this project will focus on the effect of ERK-mediated dynamic signaling on DNA methylation pattern. We will mainly study how to reconstruct the DNA methylation pattern and find the best gene expression pattern under dual constraints of maximum information transmission and minimum energy cost; the influence of DNA methylation pattern on the gene expression system processing information ability and its kinetics characteristics; the relationship between this ability and energy consumption under the constraint of DNA methylation level; the quantitative analysis of the response time under the dual constraint of DNA methylation level and external signals, etc. Through experimental data-based mathematical modeling and theoretical analysis, this project tries to reveal the essential principles on the changes of DNA methylation pattern in noisy environments. Related studies not only are helpful for understanding intracellular processes and uncovering the mechanism of biological molecules but also would have application perspective in the fields such as gene therapy and medicine.

ERK/MAPK信号转导网络传递并整合细胞内外信息，诱导细胞内ETS1蛋白水平随机涨落，促使DNA甲基化模式动态变化。定量化DNA甲基化过程与环境噪声的交互影响，明确DNA甲基化模式的生物学功能，是值得研究的生物学问题。基于现有实验数据，本项目将着重考察ERK激酶介导下，外部动态信息对DNA甲基化模式的影响，主要包括：构建DNA甲基化动态模式的数学模型，寻求在信息传递最大化且能量消耗最小化双重目标约束下的最佳基因表达图谱；DNA甲基化模式对系统处理信息的能力及其动力学特性的影响；DNA甲基化模式约束下，信息处理能力与能量消耗之间的关系；DNA甲基化水平和外部信号双重影响下，系统响应时间的定量分析等。通过基于生物实验数据的数学建模和理论分析，试图揭示噪声环境下DNA甲基化模式变化的内在原理。相关研究结果不仅有助于理解细胞内部过程进而揭示其生物分子机制，而且在基因医疗等领域具有潜在的应用前景。

DNA 甲基化动态模式是细胞表达的重要噪声源。本研究基于能量耗散最小以及表达效率最大的双目标约束下，考察基因上游结构与下游表型之间的定量关系，进而阐明DNA甲基化最佳模式，其主要的研究内容包括：1）研究了基因表达稳定性与能量代价之间的对冲权衡关系；2）考察了复杂结构的启动子活性的能量成本和平均停留时间；3）探讨了DNA环路相互作用的自由能消耗；4）多重色噪声环境扰动下系统响应的定量研究；5）基于等效拓扑网络构造下基因表型与能量耗散联系的定量研究。此外，还考察了色噪声对于系统表观遗传的调控、数据处理与机器学习方式对复杂网络的识别等方面的内容。相关的研究结果不仅有助于定量化DNA甲基化动态模式对基因表型的影响，而且在基因医疗等领域具有潜在的应用前景。