Institute for Systems Theory and Automatic Control, University of Stuttgart, Germany.
Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Germany.
FEBS J. 2021 Oct;288(19):5692-5707. doi: 10.1111/febs.15838. Epub 2021 May 1.
In recent years, epigenetic memory systems have been developed based on DNA methylation and positive feedback systems. Achieving a robust design for these systems is generally a challenging and multifactorial task. We developed and validated a novel mathematical model to describe methylation-based epigenetic memory systems that capture switching dynamics of methylation levels and methyltransferase amounts induced by different inputs. A bifurcation analysis shows that the system operates in the bistable range, but in its current setup is not robust to changes in parameters. An expansion of the model captures heterogeneity of cell populations by accounting for distributed cell division rates. Simulations predict that the system is highly sensitive to variations in temperature, which affects cell division and the efficiency of the zinc finger repressor. A moderate decrease in temperature leads to a highly heterogeneous response to input signals and bistability on a single-cell level. The predictions of our model were confirmed by flow cytometry experiments conducted in this study. Overall, the results of our study give insights into the functional mechanisms of methylation-based memory systems and demonstrate that the switching dynamics can be highly sensitive to experimental conditions.
近年来，基于 DNA 甲基化和正反馈系统，已经开发出了表观遗传记忆系统。实现这些系统的稳健设计通常是一个具有挑战性的多因素任务。我们开发并验证了一种新的数学模型，用于描述基于甲基化的表观遗传记忆系统，该系统可以捕捉不同输入诱导的甲基化水平和甲基转移酶数量的开关动力学。分岔分析表明，该系统在双稳态范围内运行，但在当前设置中，对参数变化不够稳健。通过考虑细胞分裂率的分布，该模型的扩展部分可以捕获细胞群体的异质性。模拟预测，该系统对温度变化非常敏感，温度会影响细胞分裂和锌指抑制剂的效率。温度适度降低会导致对输入信号的高度异质响应，并在单细胞水平上产生双稳态。本研究中的流式细胞术实验验证了我们模型的预测。总的来说，我们的研究结果深入了解了基于甲基化的记忆系统的功能机制，并表明开关动力学对实验条件非常敏感。
