Titration and hysteresis in epigenetic chromatin silencing

TL;DR

This paper models epigenetic chromatin silencing in yeast, revealing how protein availability and enzyme activity influence bistability, hysteresis, and gene expression, with implications for understanding gene regulation mechanisms.

Contribution

It introduces a coupled model considering protein titration effects on chromatin states, highlighting how perturbations alter epigenetic stability and hysteresis.

Findings

Hysteresis loops change qualitatively with protein abundance.

Gene expression shows nonmonotonic dependence on Sir2 activity.

Titration effects cause state transitions to become continuous.

Abstract

Epigenetic mechanisms of silencing via heritable chromatin modifications play a major role in gene regulation and cell fate specification. We consider a model of epigenetic chromatin silencing in budding yeast and study the bifurcation diagram and characterize the bistable and the monostable regimes. The main focus of this paper is to examine how the perturbations altering the activity of histone modifying enzymes affect the epigenetic states. We analyze the implications of having the total number of silencing proteins given by the sum of proteins bound to the nucleosomes and the ones available in the ambient to be constant. This constraint couples different regions of chromatin through the shared reservoir of ambient silencing proteins. We show that the response of the system to perturbations depends dramatically on the titration effect caused by the above constraint. In particular, for a certain range of overall abundance of silencing proteins, the hysteresis loop changes qualitatively with certain jump replaced by continuous merger of different states. In addition, we find a nonmonotonic dependence of gene expression on the rate of histone deacetylation activity of Sir2. We discuss how these qualitative predictions of our model could be compared with experimental studies of the yeast system under anti-silencing drugs.