表观遗传染色质沉默：双稳态和前沿传播
Epigenetic Chromatin Silencing: Bistability and Front Propagation
摘要：
组蛋白的翻译后修饰在真核生物基因调控中的作用已被广泛认识。通过可遗传的染色质修饰的基因的表观遗传沉默在高等生物的细胞命运特化中起着重要作用。我们制定了一个粗粒度的模型染色质沉默在酵母和研究的条件下，系统变得不稳定，允许不同的表观遗传状态。我们还研究了染色质的两个局部稳定状态之间的边界的动态：沉默和非沉默。该模型可用于指导一般的染色质沉默的讨论。在芽殖酵母中沉默的背景下，它帮助我们理解各种突变体的表型，其中一些突变体在没有数学模型的帮助下可能是不平凡的。一个这样的实例是降低特定组蛋白侧链的背景乙酰化速率的突变，其与Sir2p的脱乙酰化竞争。由于Sir蛋白质消耗效应而产生的负反馈引起了有趣的反直觉后果。我们的数学分析提出了不同的动力学行为可能在同一个分子模型，并指导制定更精细的假设，可以解决实验。
英文摘要：
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.
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