Portillo-Ledesma Stephanie, Schlick Tamar
Department of Chemistry, New York University, 1001 Silver, 100 Washington Square East, New York, New York, 10003, USA.
Courant Institute of Mathematical Sciences, New York University, 251 Mercer St, New York, New York, 10012, USA.
Wiley Interdiscip Rev Comput Mol Sci. 2020 Mar-Apr;10(2). doi: 10.1002/wcms.1434. Epub 2019 Aug 6.
Chromatin structure, dynamics, and function are being intensely investigated by a variety of methods, including microscopy, X-ray diffraction, nuclear magnetic resonance, biochemical crosslinking, chromosome conformation capture, and computation. A range of experimental techniques combined with modeling is clearly valuable to help interpret experimental data and, importantly, generate configurations and mechanisms related to the 3D organization and function of the genome. Contact maps, in particular, as obtained by a variety of chromosome conformation capture methods, are of increasing interest due to their implications on genome structure and regulation on many levels. In this perspective, using seven examples from our group's studies, we illustrate how molecular modeling can help interpret such experimental data. Specifically, we show how computed contact maps related to experimental systems can be used to explain structures of nucleosomes, chromatin higher-order folding, domain segregation mechanisms, gene organization, and the effect on chromatin structure of external and internal fiber parameters, such as nucleosome positioning, presence of nucleosome free regions, histone posttranslational modifications, and linker histone binding. We argue that such computations on multiple spatial and temporal scales will be increasingly important for the integration of genomic, epigenomic, and biophysical data on chromatin structure and related cellular processes.
染色质的结构、动力学和功能正通过多种方法进行深入研究，包括显微镜技术、X射线衍射、核磁共振、生化交联、染色体构象捕获和计算方法。一系列实验技术与建模相结合，对于帮助解释实验数据显然具有重要价值，而且重要的是，能够生成与基因组的三维组织和功能相关的结构和机制。特别是通过各种染色体构象捕获方法获得的接触图谱，因其在多个层面上对基因组结构和调控的影响而受到越来越多的关注。在本文中，我们以本研究小组的七个例子来说明分子建模如何有助于解释此类实验数据。具体而言，我们展示了与实验系统相关的计算接触图谱如何用于解释核小体的结构、染色质的高阶折叠、结构域分离机制、基因组织，以及外部和内部纤维参数（如核小体定位、核小体自由区域的存在、组蛋白翻译后修饰和连接组蛋白结合）对染色质结构的影响。我们认为，这种在多个空间和时间尺度上的计算对于整合关于染色质结构和相关细胞过程的基因组学、表观基因组学和生物物理数据将变得越来越重要。
