Clauvelin N, Lo P, Kulaeva O I, Nizovtseva E V, Diaz-Montes J, Zola J, Parashar M, Studitsky V M, Olson W K
Department of Chemistry and Chemical Biology, BioMaPS Institute for Quantitative Biology, Rutgers the State University of New Jersey, Piscataway, NJ 08854, USA.
J Phys Condens Matter. 2015 Feb 18;27(6):064112. doi: 10.1088/0953-8984/27/6/064112. Epub 2015 Jan 7.
The dynamic organization of chromatin plays an essential role in the regulation of gene expression and in other fundamental cellular processes. The underlying physical basis of these activities lies in the sequential positioning, chemical composition, and intermolecular interactions of the nucleosomes-the familiar assemblies of ∼150 DNA base pairs and eight histone proteins-found on chromatin fibers. Here we introduce a mesoscale model of short nucleosomal arrays and a computational framework that make it possible to incorporate detailed structural features of DNA and histones in simulations of short chromatin constructs. We explore the effects of nucleosome positioning and the presence or absence of cationic N-terminal histone tails on the 'local' inter-nucleosomal interactions and the global deformations of the simulated chains. The correspondence between the predicted and observed effects of nucleosome composition and numbers on the long-range communication between the ends of designed nucleosome arrays lends credence to the model and to the molecular insights gleaned from the simulated structures. We also extract effective nucleosome-nucleosome potentials from the simulations and implement the potentials in a larger-scale computational treatment of regularly repeating chromatin fibers. Our results reveal a remarkable effect of nucleosome spacing on chromatin flexibility, with small changes in DNA linker length significantly altering the interactions of nucleosomes and the dimensions of the fiber as a whole. In addition, we find that these changes in nucleosome positioning influence the statistical properties of long chromatin constructs. That is, simulated chromatin fibers with the same number of nucleosomes exhibit polymeric behaviors ranging from Gaussian to worm-like, depending upon nucleosome spacing. These findings suggest that the physical and mechanical properties of chromatin can span a wide range of behaviors, depending on nucleosome positioning, and that care must be taken in the choice of models used to interpret the experimental properties of long chromatin fibers.
染色质的动态组织在基因表达调控及其他基本细胞过程中起着至关重要的作用。这些活动背后的物理基础在于核小体的顺序定位、化学组成以及分子间相互作用，核小体是在染色质纤维上发现的由约150个DNA碱基对和八个组蛋白组成的常见组装体。在此，我们引入了短核小体阵列的中尺度模型和一个计算框架，使得在短染色质构建体的模拟中纳入DNA和组蛋白的详细结构特征成为可能。我们探讨了核小体定位以及阳离子N端组蛋白尾巴的有无对模拟链的“局部”核小体间相互作用和全局变形的影响。核小体组成和数量对设计的核小体阵列两端之间远程通讯的预测效应与观察效应之间的对应关系，为该模型以及从模拟结构中获得的分子见解提供了可信度。我们还从模拟中提取了有效的核小体 - 核小体势能，并将其应用于对规则重复染色质纤维的更大规模计算处理中。我们的结果揭示了核小体间距对染色质柔韧性的显著影响，DNA连接子长度的微小变化会显著改变核小体的相互作用以及整个纤维的尺寸。此外，我们发现这些核小体定位的变化会影响长染色质构建体的统计特性。也就是说，具有相同数量核小体的模拟染色质纤维表现出从高斯型到蠕虫状的聚合物行为，这取决于核小体间距。这些发现表明，染色质的物理和机械性质可以涵盖广泛的行为范围，这取决于核小体的定位，并且在选择用于解释长染色质纤维实验性质的模型时必须谨慎。
