Identifying Strong Modulators of Cellular Quiescence Depth Across Different Quiescent Cells and Conditions

ABSTRACT The proper balance and transition between cellular quiescence and proliferation are critical to tissue homeostasis, repair, and regeneration. The likelihood of quiescence-to-proliferation transition is inversely correlated with quiescence depth, and deep quiescent cells are less likely to exit quiescence and reenter the cell cycle than shallow quiescent cells. The regulatory mechanisms of quiescence depth are poorly understood but essential for developing strategies against hypo- or hyper-proliferation diseases such as aging and cancer. Our earlier studies have demonstrated that the activation threshold of the bistable Rb-E2F gene network switch (Th E2F ) controls quiescence depth. We have also identified coarse- and fine-tuning Th E2F modulators in rat embryonic fibroblasts. To examine whether other quiescent cells (including most adult stem and progenitor cells) under different environmental conditions use the same or different modulators of quiescence depth, here we studied the behaviors of 30,000 theoretical quiescent cell models that each support a functional Rb-E2F bistable switch with a unique parameter set. We found that although the vastly heterogeneous quiescent cell models exhibited no apparent parameter patterns, they converged at two alternative groups of strong quiescence-depth modulators (G1 cyclin/cdk-related and Rb/E2F complex-related). Our further machine learning (decision tree) analysis suggested that the Rb protein level and dephosphorylation rate in quiescent cells determine which modulator group to use to regulate quiescence depth.