Transcriptional Fluctuations Govern the Serum-Dependent Cell Cycle Duration Heterogeneities in Mammalian Cells

Mammalian cells exhibit a high degree of intercellular variability in cell cycle period and phase durations. However, the factors orchestrating the cell cycle duration heterogeneities remain unclear. Herein, by combining cell cycle network-based mathematical models with live single-cell imaging studies under varied serum conditions, we demonstrate that fluctuating transcription rates of cell cycle regulatory genes across cell lineages and during cell cycle progression in mammalian cells majorly govern the robust correlation patterns of cell cycle period and phase durations among sister, cousin, and mother-daughter lineage pairs. However, for the overall cellular population, alteration in the serum level modulates the fluctuation and correlation patterns of cell cycle period and phase durations in a correlated manner. These heterogeneities at the population level can be fine-tuned under limited serum conditions by perturbing the cell cycle network using a p38-signaling inhibitor without affecting the robust lineage-level correlations. Overall, our approach identifies transcriptional fluctuations as the key controlling factor for the cell cycle duration heterogeneities and predicts ways to reduce cell-to-cell variabilities by perturbing the cell cycle network regulations.