Model-based robustness and bistability analysis for methylation-based, epigenetic memory systems

Area of Science:

• Molecular Biology
• Systems Biology
• Biophysics

Background:

• Epigenetic memory systems, crucial for cellular function, are often based on DNA methylation and positive feedback loops.
• Designing robust epigenetic memory systems remains a complex challenge due to multiple interacting factors.

Purpose of the Study:

• To develop and validate a mathematical model for DNA methylation-based epigenetic memory systems.
• To analyze the switching dynamics of methylation levels and methyltransferase amounts under various inputs.
• To investigate the robustness and sensitivity of these systems to parameter changes and environmental conditions.

Main Methods:

• Developed a novel mathematical model to simulate methylation-based epigenetic memory.
• Performed bifurcation analysis to assess system stability and bistability.
• Expanded the model to incorporate cell population heterogeneity and distributed cell division rates.
• Utilized flow cytometry experiments to validate model predictions.

Main Results:

• The model demonstrated that epigenetic memory systems operate in a bistable range but are sensitive to parameter variations.
• Simulations predicted high sensitivity to temperature fluctuations, affecting cell division and repressor efficiency.
• A moderate temperature decrease induced heterogeneous cellular responses and single-cell bistability.
• Experimental validation confirmed the model's predictions regarding temperature-dependent epigenetic memory dynamics.

Conclusions:

• Methylation-based epigenetic memory systems exhibit complex switching dynamics.
• System robustness is challenged by parameter variability and environmental factors like temperature.
• Understanding sensitivity to experimental conditions is crucial for studying epigenetic memory mechanisms.