Genetic regulatory networks that count to 3

Area of Science:

• Systems Biology
• Molecular Biology
• Developmental Biology

Background:

• Sensing graded inputs is crucial for developmental decisions.
• Gene regulatory circuits control cellular responses to stimuli.
• Understanding how cells count molecular signals informs developmental processes.

Purpose of the Study:

• To model gene regulatory circuits capable of distinguishing and counting gene copy numbers (1, 2, and 3).
• To explore circuit architectures that maintain memory of the count after resetting.
• To investigate the role of circuit parameters, specifically repressive links modeled by Michaelis-Menten terms.

Main Methods:

• Computational modeling of gene regulatory circuits.
• Sampling diverse circuit architectures and parameters.
• Focusing on circuits with repressive links using Michaelis-Menten kinetics.

Main Results:

• Circuits were designed to reach distinct states for gene copy numbers 1, 2, and 3.
• Counting to 3 does not necessitate a hierarchy in Hill coefficients, unlike counting to 2 (e.g., lambda phage).
• Two primary circuit architectures were identified: one resembling vertebrate neural tube development (sonic hedgehog pathway) and a robust repressilator-based design.

Conclusions:

• Gene regulatory circuits can be engineered to perform counting functions based on gene copy number.
• Novel circuit designs offer robust counting and memory capabilities.
• These findings provide insights into biological counting mechanisms and potential synthetic biology applications.