表观遗传染色质沉默中的滴定和滞后现象
Titration and hysteresis in epigenetic chromatin silencing
摘要：
通过可遗传的染色质修饰沉默的表观遗传机制在基因调控和细胞命运规范中起主要作用。我们考虑了芽殖酵母中的表观遗传染色质沉默模型，研究了分叉图，并描述了单稳态和单稳态的特征。本文的主要重点是研究如何扰动改变组蛋白修饰酶的活性影响表观遗传状态。我们分析了沉默蛋白的总数由结合到核小体的蛋白质和周围环境中可用的蛋白质的总和给出的含义。这种限制通过环境沉默蛋白的共享库耦合染色质的不同区域。我们表明，系统的扰动的响应显着依赖于上述约束所造成的滴定效果。特别地，对于沉默蛋白的总体丰度的一定范围，滞后环定性地改变，其中一定的跳跃被不同状态的连续合并所取代。此外，我们发现Sir 2的组蛋白去乙酰化活性的速率上的基因表达的非单调依赖性。我们讨论了如何将我们的模型的这些定性预测与抗沉默药物下酵母系统的实验研究进行比较。
英文摘要：
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.
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