Nagaraj Vijayalakshmi H, Mukhopadhyay Swagatam, Dayarian Adel, Sengupta Anirvan M
BioMaPS Institute, Rutgers University, Piscataway, NJ, United States of America.
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States of America.
PLoS One. 2014 Dec 23;9(12):e113516. doi: 10.1371/journal.pone.0113516. eCollection 2014.
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.
除了基因网络开关外，DNA和组蛋白的局部表观遗传修饰在全或无的细胞决策中也起着重要作用。在这里，我们研究了一个特征明确的表观遗传染色质开关——酵母SIR系统的动力学设计，以了解表观遗传状态稳定性的起源。我们通过用组蛋白去乙酰化酶抑制剂对其进行扰动来研究该系统中的滞后现象。我们发现，SIR沉默具有非线性双稳态系统的许多特征，这与传统的遗传开关中观察到的情况类似，传统遗传开关基于少数启动子的活性，这些启动子通过其基因产物的丰度相互影响。非常值得注意的是，我们在酵母端粒沉默方面的实验在从双稳态转变为单稳态时呈现出一种非常独特的模式。特别是，在增加抑制剂浓度时，稳定沉默状态的丧失似乎并未表现出预期的鞍结行为，反而看起来像一个超临界叉形分岔。换句话说，“关闭”状态在一个阈值浓度下与“开启”状态合并为一个单一状态，这与两种状态在达到阈值之前保持不同并表现出从“关闭”到“开启”状态的不连续跳跃相反。我们认为这是沉默区域和活跃区域与动态结构域边界共存的必然结果。因此，我们研究中的实验观察结果对理解酵母及其他生物中的染色质沉默具有广泛的意义。
