Epigenetic cell memory: The gene’s inner chromatin modification circuit
Epigenetic cell memory: The gene’s inner chromatin modification circuit
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DOI：
10.1101/2022.02.02.476953
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发表时间：
2022-02
影响因子：
4.3
通讯作者：
Simone Bruno;Ruth J. Williams;D. Vecchio
中科院分区：
文献类型：
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作者：
Simone Bruno;Ruth J. Williams;D. Vecchio
表观遗传细胞记忆允许不同的基因表达模式在不同的细胞类型中持续存在，尽管有共同的基因型。虽然不同的模式可以通过转录因子（TF）的协同作用来维持，但有人提出，长期持久性取决于染色质状态。在这里，我们研究了染色质状态的动态如何影响记忆，并专注于一个生物学动机的电路基序，组蛋白和DNA修饰，介导的TF对基因表达的作用。记忆产生于三个电路组成过程的时间尺度分离：基础擦除、自动和交叉催化以及修改的补充擦除。当后两个过程比前者足够快时，电路表现出双稳态和滞后，允许激活和抑制基因状态共存，并在TF刺激去除后持续存在。记忆的持续时间是随机的，其平均值随着时间尺度分离的增加而增加，但对于被压抑的状态来说更是如此。这种不对称性源于抑制性组蛋白修饰和DNA甲基化之间的交叉催化作用，并因后者相对较慢的衰变速率而增强。然而，TF介导的正性自身调节可以重新平衡这种不对称性，甚至赋予活性状态对抑制性刺激的鲁棒性。更一般地说，通过在时间尺度分离下连接正向自调节的染色质修饰电路，出现了长期不同的基因表达模式，这也对调控环节的失败具有鲁棒性。
Epigenetic cell memory allows distinct gene expression patterns to persist in different cell types despite a common genotype. Although different patterns can be maintained by the concerted action of transcription factors (TFs), it was proposed that long-term persistence hinges on chromatin state. Here, we study how the dynamics of chromatin state affect memory, and focus on a biologically motivated circuit motif, among histones and DNA modifications, that mediates the action of TFs on gene expression. Memory arises from time-scale separation among three circuit’s constituent processes: basal erasure, auto and cross-catalysis, and recruited erasure of modifications. When the two latter processes are sufficiently faster than the former, the circuit exhibits bistability and hysteresis, allowing active and repressed gene states to coexist and persist after TF stimulus removal. The duration of memory is stochastic with a mean value that increases as time-scale separation increases, but more so for the repressed state. This asymmetry stems from the cross-catalysis between repressive histone modifications and DNA methylation and is enhanced by the relatively slower decay rate of the latter. Nevertheless, TF-mediated positive autoregulation can rebalance this asymmetry and even confers robustness of active states to repressive stimuli. More generally, by wiring positively autoregulated chromatin modification circuits under time scale separation, long-term distinct gene expression patterns arise, which are also robust to failure in the regulatory links.