论文标题
使用无拟合模型模拟人类染色体中的拓扑结构域
Simulating topological domains in human chromosomes with a fitting-free model
论文作者
论文摘要
我们讨论了人类染色体3D组织的聚合物模型。染色体由一串珠子表示,每个珠子都根据1D生物信息学数据(例如,染色质状态,组蛋白修饰,GC含量)为“彩色”。单个球体(代表双价转录因子)可以可逆地和选择性地结合具有适当颜色的珠子。在分子动力学模拟过程中,这些因子结合,串自发地折叠成环,玫瑰花结和拓扑缔合域(TADS)。该组织发生在没有远处DNA段之间或转录因子之间的任何特定相互作用的情况下。与HI-C数据的比较表明,模拟正确预测了TAD之间大多数边界的位置。该模型“无拟合”,因为它不使用HI-C数据作为输入;因此,其优势之一是,在没有现有的HI-C数据的情况下,它原则上可以用来预测给定生物或细胞系中任何感兴趣区域或整个染色体的3D组织。我们讨论如何完善这个简单的模型,包括更多的转录因子和结合位点,并正确预测收敛的CTCF结合位点之间的接触。
We discuss a polymer model for the 3D organization of human chromosomes. A chromosome is represented by a string of beads, with each bead being "colored" according to 1D bioinformatic data (e.g., chromatin state, histone modification, GC content). Individual spheres (representing bi- and multi-valent transcription factors) can bind reversibly and selectively to beads with the appropriate color. During molecular dynamics simulations, the factors bind, and the string spontaneously folds into loops, rosettes, and topologically-associating domains (TADs). This organization occurs in the absence of any specified interactions between distant DNA segments, or between transcription factors. A comparison with Hi-C data shows that simulations predict the location of most boundaries between TADs correctly. The model is "fitting-free" in the sense that it does not use Hi-C data as an input; consequently, one of its strengths is that it can -- in principle -- be used to predict the 3D organization of any region of interest, or whole chromosome, in a given organism, or cell line, in the absence of existing Hi-C data. We discuss how this simple model might be refined to include more transcription factors and binding sites, and to correctly predict contacts between convergent CTCF binding sites.