ABSTRACT

Cell-fate networks are traditionally studied within the framework of gene regulatory networks. This paradigm considers only interactions of genes through expressed transcription factors and does not incorporate chromatin modification processes. This paper introduces a mathematical model that seamlessly combines gene regulatory networks and DNA methylation (DNAm), with the goal of quantitatively characterizing the contribution of epigenetic regulation to gene silencing. The ‘Basin of Attraction percentage’ is introduced as a metric to quantify gene silencing abilities. As a case study, a computational and theoretical analysis is carried out for a model of the pluripotent stem cell circuit as well as a simplified self-activating gene model. The results confirm that the methodology quantitatively captures the key role that DNAm plays in enhancing the stability of the silenced gene state.

摘要

细胞命运网络传统上是在基因调控网络的框架内研究的。该范式仅考虑基因通过表达的转录因子的相互作用，不包括染色质修饰过程。本文介绍了一个将基因调控网络和 DNA 甲基化 (DNAm) 无缝结合的数学模型，目的是定量表征表观遗传调控对基因沉默的贡献。引入“吸引力百分比”作为量化基因沉默能力的指标。作为案例研究，对多能干细胞回路模型以及简化的自激活基因模型进行了计算和理论分析。