Abstract
In addition to gene network switches, local epigenetic modifications to DNA and histones play an important role in all-or-none cellular decision-making. Here, we study the dynamical design of a well-characterized epigenetic chromatin switch: the yeast SIR system, in order to understand the origin of the stability of epigenetic states. We study hysteresis in this system by perturbing it with a histone deacetylase inhibitor. We find that SIR silencing has many characteristics of a non-linear bistable system, as observed in conventional genetic switches, which are based on activities of a few promoters affecting each other through the abundance of their gene products. Quite remarkably, our experiments in yeast telomeric silencing show a very distinctive pattern when it comes to the transition from bistability to monostability. In particular, the loss of the stable silenced state, upon increasing the inhibitor concentration, does not seem to show the expected saddle node behavior, instead looking like a supercritical pitchfork bifurcation. In other words, the ‘off’ state merges with the ‘on’ state at a threshold concentration leading to a single state, as opposed to the two states remaining distinct up to the threshold and exhibiting a discontinuous jump from the ‘off’ to the ‘on’ state. We argue that this is an inevitable consequence of silenced and active regions coexisting with dynamic domain boundaries. The experimental observations in our study therefore have broad implications for the understanding of chromatin silencing in yeast and beyond.
Highlights
All-or-none decisions are important in many biological processes including cellfate decisions
The choice of cell fate initially depends on particular differentiating signals, but the cell often maintains the resulting fate reliably even as the original signals disappear. These fates are often associated with gene expression patterns that are heritable, a key aspect of epigenetic phenomena
We need one parameter with which we could perturb the system. Prime candidates for such perturbation are drugs that alter the activity of Sir2p [29]
Summary
All-or-none decisions are important in many biological processes including cellfate decisions. The choice of cell fate initially depends on particular differentiating signals, but the cell often maintains the resulting fate reliably even as the original signals disappear. These fates are often associated with gene expression patterns that are heritable, a key aspect of epigenetic phenomena. Mechanisms of such heritability range from genetic networks involving transcription factors to particular modifications of DNA or histones. Coordination between histone modifying enzymes and other proteins that bind to modified tails seem to play a key role in that process [2]. These deacetylated sites allow binding of the Sir3p/Sir4p complex, which, in turn, leads to recruitment of more Sir2p [3]
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