Design principles for robust multistability in coupled feedforward-feedback regulatory circuits.

Area of Science:

• Systems Biology
• Synthetic Biology
• Network Motifs

Background:

• Feedforward loops (FFLs) and feedback loops (FBLs) are essential network motifs in biological systems.
• These motifs regulate crucial cellular functions like signal filtering and state switching.
• Understanding how FBLs coupled with FFLs generate robust multistability for cellular decision-making is critical.

Purpose of the Study:

• To systematically investigate coupled FFL-FBL architectures for robust multistability.
• To explore the impact of different FFL types (AND/OR logic) and feedback edge configurations.
• To identify design principles for engineering synthetic multistable circuits.

Main Methods:

• Enumerated 729 possible circuits for four distinct FFL-FBL frameworks.
• Modeled circuits using systems of ordinary differential equations.
• Quantified robustness by simulating 100,000 random parameter sets for multistability.

Main Results:

• Positive self-activation emerged as a primary driver of multistability.
• Coherent FFLs were more conducive to multistability than incoherent ones.
• Identified specific circuit designs exhibiting robust multistability across frameworks.

Conclusions:

• Coupled FFL-FBL architectures can be engineered for robust multistability.
• Design principles involving positive self-activation and coherent motifs are highlighted.
• Findings provide guidelines for creating synthetic multistable biological circuits.