随机核小体动力学模型揭示了刺激诱导的表观基因组重塑的调控规则。
Stochastic models of nucleosome dynamics reveal regulatory rules of stimulus-induced epigenome remodeling.
机构信息
Department of Mathematics, Pohang University of Science and Technology, Pohang, South Korea.
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, Los Angeles, CA, USA.
出版信息
Cell Rep. 2022 Jul 12;40(2):111076. doi: 10.1016/j.celrep.2022.111076.
The genomic positions of nucleosomes are a defining feature of the cell's epigenomic state, but signal-dependent transcription factors (SDTFs), upon activation, bind to specific genomic locations and modify nucleosome positioning. Here we leverage SDTFs as perturbation probes to learn about nucleosome dynamics in living cells. We develop Markov models of nucleosome dynamics and fit them to time course sequencing data of DNA accessibility. We find that (1) the dynamics of DNA unwrapping are significantly slower in cells than reported from cell-free experiments, (2) only models with cooperativity in wrapping and unwrapping fit the available data, (3) SDTF activity produces the highest eviction probability when its binding site is adjacent to but not on the nucleosome dyad, and (4) oscillatory SDTF activity results in high location variability. Our work uncovers the regulatory rules governing SDTF-induced nucleosome dynamics in live cells, which can predict chromatin accessibility alterations during inflammation at single-nucleosome resolution.
核小体的基因组位置是细胞表观基因组状态的一个决定性特征，但信号依赖型转录因子（SDTFs）在激活后会结合到特定的基因组位置，并改变核小体的定位。在这里，我们利用 SDTFs 作为扰动探针，来了解活细胞中的核小体动力学。我们开发了核小体动力学的马尔可夫模型，并将其拟合到 DNA 可及性的时间序列测序数据中。我们发现：（1）与无细胞实验相比，DNA 解缠绕的动力学在细胞中显著减慢；（2）只有在缠绕和解缠绕中具有协同性的模型才能拟合可用数据；（3）当 SDTF 的结合位点位于核小体的双联体附近而非其上时，其结合能产生最高的逐出概率；（4）振荡的 SDTF 活性会导致位置高度可变性。我们的工作揭示了调控 SDTF 诱导的活细胞中核小体动力学的规则，这些规则可以预测在炎症过程中单核小体分辨率下染色质可及性的改变。
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