Modeling transcriptional regulation of the cell cycle using a novel cybernetic-inspired approach

Quantitative understanding of cellular processes, such as cell cycle and differentiation, is impeded by various forms of complexity ranging from myriad molecular players and their multilevel regulatory interactions, cellular evolution with multiple intermediate stages, lack of elucidation of cause-effect relationships among the many system players, and the computational complexity associated with the profusion of variables and parameters. In this paper, we present an elegant modeling framework based on the cybernetic concept that biological regulation is inspired by objectives embedding entirely novel strategies for dimension reduction, process stage specification through the system dynamics, and innovative causal association of regulatory events with the ability to predict the evolution of the dynamical system. The elementary step of the modeling strategy involves stage-specific objective functions that are computationally-determined from experiments, augmented with dynamical network computations involving end point objective functions, mutual information, change point detection, and maximal clique centrality. We demonstrate the power of the method through application to the mammalian cell cycle, which involves thousands of biomolecules engaged in signaling, transcription, and regulation. Starting with a fine-grained transcriptional description obtained from RNA sequencing measurements, we develop an initial model, which is then dynamically modeled using the cybernetic-inspired method (CIM), utilizing the strategies described above. The CIM is able to distill the most significant interactions from a multitude of possibilities. In addition to capturing the complexity of regulatory processes in a mechanistically causal and stage-specific manner, we identify the functional network modules, including novel cell cycle stages. Our model is able to predict future cell cycles consistent with experimental measurements. We posit that this state-of-the-art framework has the promise to extend to the dynamics of other biological processes, with a potential to provide novel mechanistic insights. STATEMENT OF SIGNIFICANCECellular processes like cell cycle are overly complex, involving multiple players interacting at multiple levels, and explicit modeling of such systems is challenging. The availability of longitudinal RNA measurements provides an opportunity to "reverse-engineer" for novel regulatory models. We develop a novel framework, inspired using goal-oriented cybernetic model, to implicitly model transcriptional regulation by constraining the system using inferred temporal goals. A preliminary causal network based on information-theory is used as a starting point, and our framework is used to distill the network to temporally-based networks containing essential molecular players. The strength of this approach is its ability to dynamically model the RNA temporal measurements. The approach developed paves the way for inferring regulatory processes in many complex cellular processes.