Epigenetic cell memory: The gene's inner chromatin modification circuit

Epigenetic cell memory allows distinct gene expression patterns to persist in different cell types despite a common genotype. Although different patterns can be maintained by the concerted action of transcription factors (TFs), it was proposed that long-term persistence hinges on chromatin state. Here, we study how the dynamics of chromatin state affect memory, and focus on a biologically motivated circuit motif, among histones and DNA modifications, that mediates the action of TFs on gene expression. Memory arises from time-scale separation among three circuit's constituent processes: basal erasure, auto and cross-catalysis, and recruited erasure of modifications. When the two latter processes are sufficiently faster than the former, the circuit exhibits bistability and hysteresis, allowing active and repressed gene states to coexist and persist after TF stimulus removal. The duration of memory is stochastic with a mean value that increases as time-scale separation increases, but more so for the repressed state. This asymmetry stems from the cross-catalysis between repressive histone modifications and DNA methylation and is enhanced by the relatively slower decay rate of the latter. Nevertheless, TF-mediated positive autoregulation can rebalance this asymmetry and even confers robustness of active states to repressive stimuli. More generally, by wiring positively autoregulated chromatin modification circuits under time scale separation, long-term distinct gene expression patterns arise, which are also robust to failure in the regulatory links. Author summaryEpigenetic cell memory ensures that cells are locked into specialized functions for the life-time of an organism. Phenotype loss is often associated with disease, such as cancer, and also required for artificially reprogramming cells from one type to another. Chromatin state, determined by histone modifications and DNA methylation, has recently appeared as a key mediator of epigenetic cell memory. However, a mechanistic understanding of how the dynamics of chromatin state affect the temporal duration of this memory is lacking. Here, we developed and analyzed a theoretical framework that includes these dynamics in gene regulation. Our results show that when both recruited erasure and auto/cross-catalysis among histone modifications and DNA methylation are sufficiently slower than basal erasure of all modifications, loss of cell memory will occur. Our mathematical formulas show how the parameters capturing these time scales depend on the abundance of methyl-DNA-binding proteins, on writers, erasers, and readers of nucleosome modifications, and on cell division time. With this information, one may design experimental interventions to either enforce phenotypic plasticity or re-lock phenotypes in aberrant cells.