Cooperative stabilization of the SIR complex provides robust epigenetic memory in a model of SIR silencing in Saccharomyces cerevisiae

Abstract

How alternative chromatin-based regulatory states can be made stable and heritable in order to provide robust epigenetic memory is poorly understood. Here, we develop a stochastic model of the silencing system in Saccharomyces cerevisiae that incorporates cooperative binding of the repressive SIR complex and anti-silencing histone modifications, in addition to positive feedback in Sir2 recruitment. The model was able to reproduce key features of SIR regulation of an HM locus, including heritable bistability, dependence on the silencer elements, and sensitivity to SIR dosage. We found that antisilencing methylation of H3K79 by Dot1 was not needed to generate these features, but acted to reduce spreading of SIR binding, consistent with its proposed role in containment of silencing. In contrast, cooperative inter-nucleosome interactions mediated by the SIR complex were critical for concentrating SIR binding around the silencers in the absence of barriers, and for providing bistability in SIR binding. SIR-SIR interactions magnify the cooperativity in the Sir2-histone deacetylation positive feedback reaction and complete a double-negative feedback circuit involving antisilencing modifications. Thus, our modelling underscores the potential importance of cooperative interactions between nucleosome-bound complexes both in the SIR system and in other chromatin-based complexes in epigenetic regulation.