Molecular and Systems Analysis of a Cis-encoded Epigenetic Switch

Cherry Auditorium, Kirk Hall

Epigenetic control of the stability of silenced and active gene expression states is an important but poorly understood event in cell-fate decisions. Here, I show that the yeast gene FLO11 is epigenetically controlled and that the trans regulators of FLO11 control different combinations of fast and slow promoter transition rates, allowing cells to effectively modulate the distribution of gene expression and phenotypes within a clonal population in response to upstream signals. Next, I demonstrate how multiple fast molecular events that occur at a gene promoter can lead to an overall slow step. At the FLO11 promoter, I found at least two pathways that recruit histone deacetylases to the promoter and in vivo association between the core promoter and -1.2 kb site are necessary for a stable silenced state. To generate a stable active state without disrupting the stable silenced state, the activator Msn1p forms an alternate promoter conformation, where the core promoter instead associates with the promoter and terminator regions of the non-coding RNA located farther upstream on the FLO11 promoter. Predictions of silenced and active state stabilities at FLO11 from simulations of a simple biophysical model for nucleosome modifications agree well with experimental results. Together, the results suggest that multiple fast, stochastic steps at the promoter are required to transition between the silenced and active states at FLO11, leading to an overall slow step in cis. Future work to incorporate other cis events in the biophysical model and to determine individual rate parameters will be needed to develop more generalized models to ultimately predict epigenetic gene expression at a genome-wide scale.