Slow Chromatin Dynamics Allow Polycomb Target Genes to Filter Fluctuations in Transcription Factor Activity.
Slow Chromatin Dynamics Allow Polycomb Target Genes to Filter Fluctuations in Transcription Factor Activity.
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DOI：
10.1016/j.cels.2017.02.013
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发表时间：
2017-04-26
期刊：
影响因子：
9.3
通讯作者：
Howard M
中科院分区：
文献类型：
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作者：
Berry S;Dean C;Howard M
多梳抑制复合物2（PRC 2）靶向的基因由染色质修饰顺式调节，也由可扩散的调节因子（如转录因子）反式调节。在这里，我们介绍了一个数学模型，其中转录直接拮抗Polycomb沉默，从而将这些顺式和反式调控输入基因表达。最近的实验数据表明，PRC 2介导的抑制性染色质修饰积累非常缓慢的模型参数化。该模型产生了自我延续的、非活性的和抑制的染色质状态，这些状态通过DNA复制持续存在，从而确保了当前染色质状态的高保真传输。然而，足够强的、持续的转录激活或抑制促进活性和抑制的染色质状态之间的转换。我们观察到，当染色质修饰动力学缓慢时，转录激活或抑制的瞬时脉冲被有效地过滤，从而保留表观遗传记忆。因此，噪声过滤依赖于缓慢的染色质动力学，并可能代表PRC 2为基础的调节的重要功能。转录拮抗沉默的染色质的鲁棒性PRC 2模型定量拟合实验H3 K27 me 3积累的缓慢速率染色质状态可通过持续的转录激活或抑制来切换缓慢的H3 K27甲基化动力学使PRC 2靶能够过滤反式调节噪声我们提出了一个理论模型，其中反式作用和染色质-基础基因调控通过转录过程机械地整合。该模型提供了深入了解染色质如何可以响应传统的反式因子介导的转录调控，但也基于自我永存顺式表观遗传记忆，并建议染色质在过滤反式调节器的波动的作用。
Genes targeted by Polycomb repressive complex 2 (PRC2) are regulated in cis by chromatin modifications and also in trans by diffusible regulators such as transcription factors. Here, we introduce a mathematical model in which transcription directly antagonizes Polycomb silencing, thereby linking these cis- and trans-regulatory inputs to gene expression. The model is parameterized by recent experimental data showing that PRC2-mediated repressive chromatin modifications accumulate extremely slowly. The model generates self-perpetuating, bistable active and repressed chromatin states that persist through DNA replication, thereby ensuring high-fidelity transmission of the current chromatin state. However, sufficiently strong, persistent activation or repression of transcription promotes switching between active and repressed chromatin states. We observe that when chromatin modification dynamics are slow, transient pulses of transcriptional activation or repression are effectively filtered, such that epigenetic memory is retained. Noise filtering thus depends on slow chromatin dynamics and may represent an important function of PRC2-based regulation. Robust bistable model of chromatin in which transcription antagonizes silencing Quantitative fit to experimental slow rate of H3K27me3 accumulation Chromatin states are switchable by persistent transcriptional activation or repression Slow H3K27 methylation dynamics enable PRC2 targets to filter trans-regulatory noise We propose a theoretical model in which trans-acting and chromatin-based gene regulation are mechanistically integrated by the process of transcription. The model provides insight into how chromatin can respond to conventional trans-factor-mediated transcriptional regulation yet also underlie self-perpetuating cis epigenetic memory and suggests a role for chromatin in filtering fluctuations of trans regulators.