Subtle alteration in transcriptional memory governs the lineage-level cell cycle duration heterogeneities of mammalian cells

Cell cycle duration heterogeneities within a malignant tumor significantly reduce the therapeutic efficacy of cancer treatment. However, identifying factors governing such heterogeneities remains challenging. Herein, we perform a computational modeling study to demonstrate that correlated fluctuations of the inherited transcription rates during cell cycle progression and their random resetting in mitosis are sufficient to account for the experimentally observed cell cycle duration correlation patterns for cell lineage pairs. The model elucidates that the variations in the transcriptional inheritance pattern dictate the extent of the cousin-mother inequality phenomenon in a cell-type-dependent manner. Intriguingly, the model predicts that a reduction in cousin-mother inequality for a fixed mean cell cycle duration can lead to a lowering of the cell cycle duration variabilities at the population level which may have a therapeutic implication. Overall, our study elucidates that correlated transcriptional fluctuations can be the sole governing factor in orchestrating the cell cycle duration heterogeneities.