Analytical and computational study of the stochastic behavior of a chromatin modification circuit
Analytical and computational study of the stochastic behavior of a chromatin modification circuit
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染色质修饰电路随机行为的分析和计算研究
DOI：
10.1109/cdc51059.2022.9992654
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Del Vecchio, Domitilla
中科院分区：
文献类型：
--
作者：
Bruno, Simone;Williams, Ruth J.;Del Vecchio, Domitilla
多细胞生物允许具有相同遗传密码的细胞在生物体的整个生命中保持不同身份的特性被称为表观遗传细胞记忆（ECM）。最近，染色质修饰似乎在ECM中具有关键作用。在这里，我们进行随机分析的染色质修饰电路，以确定在何种程度上，该系统可以保持一个稳定的稳态，在面对噪声的主要系统过程之间的时间尺度分离的效果。为此，我们首先得到一个简化的电路模型，并确定一个解析表达式的固定概率分布和抑制和活性染色质状态之间的切换时间。然后，我们验证这些分析结果与随机模拟的原始全套反应。我们的研究结果表明，当所有染色质标记的基础衰减相对于所有标记的自动和交叉催化以及招募擦除足够慢时，固定分布显示双峰性，具有对应于活性和抑制状态的两个集中峰，但偏向于抑制状态。根据这些结果，较慢的基础衰减延长了活性和抑制状态的记忆，更广泛地说，这表明了基因表达状态持久记忆的关键设计原则。
The property of multicellular organisms that allows cells with the same genetic code to maintain distinct identities for the entire life of the organism is known as epigenetic cell memory (ECM). Recently, chromatin modifications have appeared to have a key role in ECM. Here, we conduct a stochastic analysis of a chromatin modification circuit to determine the effect of time scale separation among principal system processes on the extent to which the system can keep a stable steady state in the face of noise. To this end, we first obtain a reduced circuit model and determine an analytical expression for both the stationary probability distribution and the switching time between repressed and active chromatin states. Then, we validate these analytical results with stochastic simulations of the original full set of reactions. Our results show that when the basal decay of all chromatin marks is sufficiently slower with respect to the auto and cross-catalysis and the recruited erasure of all the marks, the stationary distribution shows bimodality, with two concentrated peaks in correspondence of the active and repressed states, but biased towards the repressed state. In accordance with these results, slower basal decay extends the memory of the active and repressed states, suggesting, more broadly, a critical design principle for long-lasting memory of gene expression states.