Identification of regulatory variables for state transition of biological networks

Attractors represent steady states of biological networks. Recent studies have shown that regulatory variables can be used to steer a network state transition from an undesired attractor, such as a cancerous state, to a desired healthy one. Therefore, it is important to identify the regulatory variables and determine their time-dependent profile for state transition of a given network. However, this is a challenging task since regulatory variables have to be identified among numerous candidates in a large-scale biological network. In this study, we developed a new method for identifying regulatory variables in large-scale biological networks for the purpose of state transition. As a result, a set of optimal regulatory variables can be determined based on formulating and solving a mixed-integer nonlinear dynamic optimization problem. A relaxation scheme is used to overcome the difficulties in solving this complex problem containing a large number of binary variables. The solution to this problem simultaneously identifies the optimal regulatory variables, provides strength of regulatory interactions, and obtains the minimal control time to realize the required state transition. In addition, by adjusting the objective function, various combinations of the strength of regulatory interactions and the transition time can be achieved according to the requirement for disease therapy. Results of three case studies (a myeloid differentiation regulatory network, a cancer gene regulatory network, and a T-LGL signaling network) demonstrate the efficacy of the proposed approach. Therefore, this study establishes an appropriate framework for identifying the regulatory variables for state transition of complex biological networks.