Predicting three-dimensional genome organization with chromatin states
Predicting three-dimensional genome organization with chromatin states
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DOI：
10.1371/journal.pcbi.1007024
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发表时间：
2019-06-01
影响因子：
4.3
通讯作者：
Zhang, Bin
中科院分区：
文献类型：
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作者：
Qi, Yifeng;Zhang, Bin
我们引入了一个计算模型来模拟染色质的结构和动力学。从可用于数百种细胞类型的一维基因组学和表观基因组学数据开始，该模型能够以5千碱基分辨率从头预测染色质结构。模拟的染色质结构概括了基因组组织的已知特征，包括染色质环、拓扑相关结构域（TADs）和区室的形成，并且与染色体构象捕获实验和超分辨率显微镜测量的定量一致。预测结构集合的详细表征揭示了染色质环的动态灵活性和相邻tad之间的串扰存在。对模型能量函数的分析揭示了不同长度尺度下染色质折叠的不同机制，并表明需要超越简单的a /B隔室类型，使用聚合物模拟来预测调节元件之间的特定接触。三维基因组组织有望在调控基因表达和建立细胞命运中发挥关键作用，并激发了许多创新实验技术的发展。尽管取得了重大进展，但高分辨率构建染色体结构仍然具有挑战性。根据Zhang和Wolynes首创的最大熵方法，我们开发了一个预测模型并参数化了一个力场，利用全基因组染色体构象捕获数据（Hi-C）来研究染色质结构和动力学。该模型从包括组蛋白修饰谱和CTCF结合位点在内的一维序列信息出发，以5kb的分辨率预测染色体结构，从而建立基因组的序列-结构关系。与同类方法相比，该模型的一个显著优势是它能够研究启动子和增强子之间的远程特定接触，以及为环、tad和隔室构建高分辨率结构。此外，该模型被证明可以跨染色体和细胞类型进行转移，从而为利用现有的表观基因组学而不是Hi-C数据对数百种细胞类型的基因组组织进行从头预测提供了机会。
We introduce a computational model to simulate chromatin structure and dynamics. Starting from one-dimensional genomics and epigenomics data that are available for hundreds of cell types, this model enables de novo prediction of chromatin structures at five-kilo-base resolution. Simulated chromatin structures recapitulate known features of genome organization, including the formation of chromatin loops, topologically associating domains (TADs) and compartments, and are in quantitative agreement with chromosome conformation capture experiments and super-resolution microscopy measurements. Detailed characterization of the predicted structural ensemble reveals the dynamical flexibility of chromatin loops and the presence of cross-talk among neighboring TADs. Analysis of the model's energy function uncovers distinct mechanisms for chromatin folding at various length scales and suggests a need to go beyond simple A/B compartment types to predict specific contacts between regulatory elements using polymer simulations.Author summary Three-dimensional genome organization is expected to play crucial roles in regulating gene expression and establishing cell fate, and has inspired the development of numerous innovative experimental techniques for its characterization. Though significant progress has been made, it remains challenging to construct chromosome structures at high resolution. Following the maximum entropy approach pioneered by Zhang and Wolynes, we developed a predictive model and parameterized a force field to study chromatin structure and dynamics using genome-wide chromosome conformation capture data (Hi-C). Starting from one-dimensional sequence information that includes histone modification profiles and CTCF binding sites, this model predicts chromosome structure at a 5kb resolution, thus establishing a sequence-structure relationship for the genome. A significant advantage of this model over comparable approaches is its ability to study long-range specific contacts between promoters and enhancers, in addition to building high-resolution structures for loops, TADs and compartments. Furthermore, the model is shown to be transferable across chromosomes and cell types, thus opens up the opportunity to carry out de novo prediction of genome organization for hundreds of cell types with available epigenomics but not Hi-C data.