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

Abstract

Cell cycle duration heterogeneities within a malignant tumor significantly reduce the therapeutic efficacy of cancer treatment. However, identifying factors governing such heterogeneities remains challenging. Here, we demonstrate that correlated fluctuations of the inherited transcription rates during cell cycle progression in combination with the random resetting of them during mitosis are sufficient to account for the experimentally observed cell cycle duration correlation patterns for daughter-daughter, mother-daughter, and cousin-cousin cell lineage pairs. The model elucidates that the variations in the transcriptional inheritance pattern dictate the extent of the cousin-mother inequality phenomenon. It further predicts that the longer the cell cycle duration, the lower will be the lineage pair correlations. However, higher S-G2-M phase duration will only increase daughter-daughter and mother-daughter correlations, hence, reducing the extent of cousin-mother inequality. Overall, the model shows how alteration of the inherited transcriptional fluctuations across lineages finetunes the lineage-level heterogeneities.