A Reference-Free Molecular Feedback Controller for Inducing Sustained Oscillations in Gene Regulatory Networks

Britto Bisso F.; Rengifo-Lozano S.; Dey S.; Stan G.-B.; Cuba Samaniego C. · IEEE Control Systems Letters (2026) · DOI: 10.1109/lcsys.2026.3704396

Resumen

Periodic behavior is a widespread biological phenomenon that occurs on multiple spatiotemporal scales, where upstream stimuli are encoded into dynamic intracellular signals. Restoring rhythmic dynamics after perturbations, or inducing them in otherwise steady-state systems, typically requires redesigning the underlying network, limiting scalability. Here we propose a reference-free molecular feedback controller built from the Incoherent Feedforward Loop (IFFL) motif that destabilizes the steady state of a non-oscillating system into sustained oscillations. We apply the controller to a self-inhibiting gene and show, through a Hopf bifurcation analysis, that sustained oscillations are induced in the fast sequestration regime when the indirect production branch of the IFFL motif dominates the direct one, and the actuation gain is sufficiently large relative to the process. Numerical simulations validate these conditions and characterize the robustness of the resulting oscillations, revealing that the period is robust to parametric perturbations while the amplitude is sensitive. Ultimately, we explore whether the same IFFL architecture extends to higher-dimensional processes by applying it, as a case study, to a negative feedback system in its non-oscillatory regime.

Instituciones: Universidad Nacional de Trujillo