(277d) Tuning Gene Expression Hetereogeneity with Cis-Encoded Epigenetic Switches

Epigenetic switches encode their state information either locally, often via covalent modification of DNA or histones; or globally, usually in the level of a trans-regulatory factor. Here we examine how the regulation of local epigenetic switches controls the extent of heterogeneity in gene expression, which is ultimately tied to phenotypic diversity in a population. We show that two copies of a locally encoded epigenetic switch, the FLO11 locus in S. cerevisiae, switch between a silenced and competent promoter state in a random and independent fashion. Using a stochastic kinetic model, we further quantify the effect trans regulators have on the slow and fast transitions between promoter states associated with epigenetic and conventional regulation of FLO11. We find different classes of regulators affect epigenetic, conventional, or both forms of regulation. Distributing the task of epigenetic and conventional regulation represents a potent strategy that offers cells flexibility in shaping the distribution of gene expression within a population. We further investigate the basic architecture of the FLO11 promoter to understand the molecular basis of the stability of the silenced and competent promoter states. A systems-level analysis of this complex promoter reveals basic strategies for increasing stability similar to signal-transduction networks. Finally, we discuss possible applications of local, cis-encoded epigenetic switches like FLO11 in synthetic biology and metabolic engineering.