Two-way feedback between chromatin compaction and histone modification state explains S. cerevisiae heterochromatin bistability.
Two-way feedback between chromatin compaction and histone modification state explains S. cerevisiae heterochromatin bistability.
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染色质压缩和组蛋白修饰状态之间的双向反馈解释了酿酒酵母异染色质双稳定性。
DOI：
10.1101/2023.08.12.552948
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Howard,Martin
中科院分区：
文献类型：
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作者：
Miangolarra,AnderMovilla;Saxton,DanielS;Yan,Zhi;Rine,Jasper;Howard,Martin
紧密染色质与基因沉默密切相关，部分原因是立体遮蔽了启动子的通路，抑制了转录因子的结合，阻止了聚合酶有效地转录基因。在这里，我们提出了一个更广泛的观点：染色质压缩既可以是组蛋白修饰状态的原因，也可以是组蛋白修饰状态的结果，这种紧密的双向相互作用可以支持双稳转录状态。为了验证这一理论，我们开发了一个用于酿酒酵母HMR基因座动态变化的数学模型，该模型包括激活组蛋白修饰、沉默蛋白质和动态的、乙酰化依赖的三维基因座大小。染色质紧凑增强了沉默蛋白的结合，这反过来又反馈到移除激活的组蛋白修饰，导致进一步的紧凑。模型的双稳态输出与先前的定量数据很好地吻合，包括从表达状态到沉默状态的转换速率，反之亦然，以及基因座内的蛋白质结合水平。然后，我们通过预测基因座遗传长度增加时转换率的变化来测试该模型，并进行了实验验证。这种染色质压缩和组蛋白修饰状态之间的双向反馈可能是许多位点的重要调节机制。
Compact chromatin is closely linked with gene silencing in part by sterically masking access to promoters, inhibiting transcription factor binding and preventing polymerase from efficiently transcribing a gene. Here, we propose a broader view: chromatin compaction can be both a cause and a consequence of the histone modification state, and this tight bidirectional interaction can underpin bistable transcriptional states. To test this theory, we developed a mathematical model for the dynamics of the HMR locus in S. cerevisiae, that incorporates activating histone modifications, silencing proteins and a dynamic, acetylation-dependent, three-dimensional locus size. Chromatin compaction enhances silencer protein binding, which in turn feeds back to remove activating histone modifications, leading to further compaction. The bistable output of the model was in good agreement with prior quantitative data, including switching rates from expressed to silent states, and vice versa, and protein binding levels within the locus. We then tested the model by predicting changes in switching rates as the genetic length of the locus was increased, which were then experimentally verified. This bidirectional feedback between chromatin compaction and the histone modification state may be an important regulatory mechanism at many loci.