Miangolarra Ander Movilla, Saxton Daniel S, Yan Zhi, Rine Jasper, Howard Martin
Dept. of Computational and Systems Biology, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
Dept. of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
bioRxiv. 2023 Aug 14:2023.08.12.552948. doi: 10.1101/2023.08.12.552948.
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 , 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.
紧密的染色质与基因沉默密切相关，部分原因是它在空间上掩盖了启动子的可及性，抑制转录因子结合，并阻止聚合酶有效地转录基因。在此，我们提出一个更广泛的观点：染色质压缩可以既是组蛋白修饰状态的原因，也是其结果，这种紧密的双向相互作用可以支撑双稳态转录状态。为了验证这一理论，我们针对酵母中HMR位点的动力学建立了一个数学模型，该模型纳入了激活组蛋白修饰、沉默蛋白以及一个动态的、依赖乙酰化的三维位点大小。染色质压缩增强了沉默蛋白的结合，这反过来又反馈以去除激活组蛋白修饰，导致进一步压缩。该模型的双稳态输出与先前的定量数据高度一致，包括从表达状态到沉默状态以及反之的转换率，以及位点内的蛋白结合水平。然后，我们通过预测随着位点的基因长度增加时转换率的变化来测试该模型，这些预测随后得到了实验验证。染色质压缩与组蛋白修饰状态之间的这种双向反馈可能是许多位点的一种重要调控机制。
