Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
Center for Eukaryotic Gene Regulation, The Pennsylvania State University, University Park, Pennsylvania, United States of America.
PLoS Comput Biol. 2021 Jan 11;17(1):e1008560. doi: 10.1371/journal.pcbi.1008560. eCollection 2021 Jan.
Nucleosome positioning in the genome is essential for the regulation of many nuclear processes. We currently have limited capability to predict nucleosome positioning in vivo, especially the locations and sizes of nucleosome depleted regions (NDRs). Here, we present a thermodynamic model that incorporates the intrinsic affinity of histones, competitive binding of sequence-specific factors, and nucleosome remodeling to predict nucleosome positioning in budding yeast. The model shows that the intrinsic affinity of histones, at near-saturating histone concentration, is not sufficient in generating NDRs in the genome. However, the binding of a few factors, especially RSC towards GC-rich and poly(A/T) sequences, allows us to predict ~ 66% of genome-wide NDRs. The model also shows that nucleosome remodeling activity is required to predict the correct NDR sizes. The validity of the model was further supported by the agreement between the predicted and the measured nucleosome positioning upon factor deletion or on exogenous sequences introduced into yeast. Overall, our model quantitatively evaluated the impact of different genetic components on NDR formation and illustrated the vital roles of sequence-specific factors and nucleosome remodeling in this process.
核小体在基因组中的定位对于许多核过程的调控至关重要。我们目前预测体内核小体定位的能力有限，特别是核小体缺失区域（NDR）的位置和大小。在这里，我们提出了一个热力学模型，该模型将组蛋白的固有亲和力、序列特异性因子的竞争结合和核小体重塑结合起来，以预测出芽酵母中的核小体定位。该模型表明，在接近饱和的组蛋白浓度下，组蛋白的固有亲和力不足以在基因组中产生 NDR。然而，少数因子的结合，特别是 RSC 与富含 GC 和多(A/T)序列的结合，使我们能够预测约 66%的全基因组 NDR。该模型还表明，核小体重塑活性是预测正确 NDR 大小所必需的。该模型的有效性还通过在因子缺失或在酵母中引入外源序列后，预测和测量的核小体定位之间的一致性得到了进一步支持。总的来说，我们的模型定量评估了不同遗传成分对 NDR 形成的影响，并说明了序列特异性因子和核小体重塑在这一过程中的重要作用。
