The accurate control of gene expression is essential for cell differentiation during development but how do heterogeneous and fluctuating gene expression levels influence cell fate choices? Here (p. ), using a novel quantitative and high-content imaging platform, Jonathon Chubb and colleagues investigate how various cell- and population-based features are coupled to Nanog reporter expression in mouse embryonic stem cells (ESCs). They first show that cell cycle times are heterogeneous within ESCs but correlate with Nanog reporter expression; low expression levels are found in both long and short cell cycles but reporter expression tends to be highest in longer cycles. The transition to ground-state pluripotency (triggered by 2i treatment), they report, correlates with longer and more variable cell cycle times. Looking at lineage history, the researchers further reveal that all cells within a lineage are strongly related with regards to both cell cycle times and reporter expression. Modelling further suggests that some element of the cell environment plays a role in stabilising gene expression between generations. Finally, the researchers highlight a correlation between cell density and both cell cycle behaviour and reporter gene expression. Based on these and other findings, the authors propose that simple deterministic views of stem cell states need rethinking.
