Heritable Stochastic Switching Revealed by Single-Cell Genealogy

The partitioning and subsequent inheritance of cellular factors like proteins and RNAs is a ubiquitous feature of cell division. However, direct quantitative measures of how such nongenetic inheritance affects subsequent changes in gene expression have been lacking. We tracked families of the yeast Saccharomyces cerevisiae as they switch between two semi-stable epigenetic states. We found that long after two cells have divided, they continued to switch in a synchronized manner, whereas individual cells have exponentially distributed switching times. By comparing these results to a Poisson process, we show that the time evolution of an epigenetic state depends initially on inherited factors, with stochastic processes requiring several generations to decorrelate closely related cells. Finally, a simple stochastic model demonstrates that a single fluctuating regulatory protein that is synthesized in large bursts can explain the bulk of our results. : When cells divide, not only DNA but an entire pattern of gene expression can be passed from mother to daughter cell. Once cell division is complete, random processes cause this pattern to change, with closely related cells growing less similar over time. We measured inheritance of a dynamic gene-expression state in single yeast cells. We used an engineered network where individual cells switch between two semi-stable states (ON and OFF), even in a constant environment. Several generations after cells have physically separated, many pairs of closely related cells switch in near synchrony. We quantified this effect by measuring how likely a mother cell is to have switched given that the daughter cell has already switched. This yields a conditional probability distribution that is very different from the exponential one found in the entire population of switching cells. We measured the extent to which this correlation between switching cells persists by comparing our results with a model Poisson process. Together, these findings demonstrate the inheritance of a dynamic gene expression state whose post-division changes include both random factors arising from noise as well as correlated factors that originate in two related cells' shared history. Finally, we constructed a model that demonstrates that our major findings can be explained by burst-like fluctuations in the levels of a single regulatory protein. When cells divide, each daughter cell inherits a share of the contents of the mother. If the contents include a regulatory system with a feedback loop, sister cells switch states in synchrony.