Epigenetic Chromatin Silencing: Bistability and Front Propagation

TL;DR

This paper presents a mathematical model of chromatin silencing in yeast, exploring bistability and boundary dynamics, providing insights into mutant phenotypes and guiding experimental hypotheses in epigenetic regulation.

Contribution

It introduces a coarse-grained model capturing bistability and boundary dynamics in chromatin silencing, linking molecular mechanisms to epigenetic states.

Findings

Bistability allows for silenced and unsilenced chromatin states.

Mutations affecting acetylation rates can produce counter-intuitive effects.

The model explains mutant phenotypes and suggests new experimental directions.

Abstract

The role of post-translational modification of histones in eukaryotic gene regulation is well recognized. Epigenetic silencing of genes via heritable chromatin modifications plays a major role in cell fate specification in higher organisms. We formulate a coarse-grained model of chromatin silencing in yeast and study the conditions under which the system becomes bistable, allowing for different epigenetic states. We also study the dynamics of the boundary between the two locally stable states of chromatin: silenced and unsilenced. The model could be of use in guiding the discussion on chromatin silencing in general. In the context of silencing in budding yeast, it helps us understand the phenotype of various mutants, some of which may be non-trivial to see without the help of a mathematical model. One such example is a mutation that reduces the rate of background acetylation of particular histone side-chains that competes with the deacetylation by Sir2p. The resulting negative feedback due to a Sir protein depletion effect gives rise to interesting counter-intuitive consequences. Our mathematical analysis brings forth the different dynamical behaviors possible within the same molecular model and guides the formulation of more refined hypotheses that could be addressed experimentally.