Transition probability in cell proliferation, stochasticity in cell differentiation, and the restriction point of the cell cycle in one package

Abstract

Clonal cells are known to display stochastically varying interdivision times (IMT) and stochastic choices of cell fates. These features are suggested in the present paper to stem from discrete transitions of genes between different modes of their engagement in transcription. These transitions are explained by stochastic events of assembly/disassembly of huge ensembles of transcription factors needed to built-up gene-specific transcription preinitiation complexes (PIC). The time required to assemble a PIC at a gene promoter by random collisions of numerous proteins may be long enough to be comparable with the cell cycle. Independently published findings are reviewed to show that active genes may display discontinuous patterns of transcriptional output consistent with stochastically varying periods of PIC presence or absence at their promoters, and that these periods may reach several hours. This timescale matches the time needed for synchronised clonal cells to pass the restriction point (RP) of the cell cycle. RP is suggested to correspond to cell state where cell fate is determined by competing discrete transcriptional events. Cell fate choice depends on the event that, by chance, has outpaced other events able to commit the cell to alternative fates. Simple modelling based on these premises is consistent with general features of cell kinetics, including RP passage dependance on mitogenic stimulation, IMT distributions conformance to exponentially modified Gaussian, the limited proliferative potential of untransformed cells, relationships between changes in cell proliferation and differentiation, and bimodal distributions of cells over expression levels of genes involved in stem cell differentiation.