Barriers and Silencers: A Theoretical Toolkit for Control and Containment of Nucleosome-Based Epigenetic States

Positive feedback in nucleosome modification has been proposed to allow large chromatin regions to exist stably and heritably in distinct expression states. However, modeling has shown that such epigenetic bistability requires that modifying enzymes recruited by nucleosomes are active on distant nucleosomes, potentially allowing uncontrollable spreading of modification. By modeling the silencing of mating-type loci in Saccharomyces cerevisiae, we show that a modification reaction that combines a long-range component and a locally acting component can provide bistability and can be blocked by simple barriers that interrupt the nucleosome chain. We find that robust containment of the silenced region could be achieved by the presence of a number of weak simple barriers in the surrounding chromatin and a limited capacity of the positive feedback reaction. In addition, we show that the state of the silenced region can be regulated by silencer elements acting only on neighboring nucleosomes. Thus, a relatively simple set of nucleosome-modifying enzymes and recognition domains is all that is needed to make chromatin-based epigenetics useful and safe.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (267 K)Download as PowerPoint slideHighlights► A ‘global–local’ positive feedback reaction in histone modification could result in stable and heritable alternative states controllable by silencer elements, prevention of spreading by simple gaps in the nucleosome chain, and robust containment by multiple weak barriers and a limited reaction.