Li Hanshuang, Ta Na, Long Chunshen, Zhang Qiutang, Li Siyu, Liu Shuai, Yang Lei, Zuo Yongchun
State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock, College of Life Sciences, Inner Mongolia University, Hohhot 010070, China.
Inner Mongolia Key Laboratory of Social Computing and Data Processing, College of Computer Science, Inner Mongolia University, Hohhot 010020, China.
Comput Struct Biotechnol J. 2019 Sep 11;17:1226-1233. doi: 10.1016/j.csbj.2019.09.002. eCollection 2019.
Understanding the target regulation between pioneer factor and its binding genes is crucial for improving the efficiency of TF-mediated reprogramming. Oct4 as the only one factor that cannot be substituted by other POU members, it is urgent need to develop a quantitative model for describing the spatial binding pattern with its target genes. The dynamic profiles of pioneer factor Oct4-binding showed that the major wave occurs at the intermediate stage of cell reprogramming (from day 7 to day 15), and the promoter is the preferred targeting regions. The Oct4-binding distributions perform significant chromosome bias. The overall enrichment on chromosome 1-11 is higher than that on the others. The dramatic event of TF-mediated reprogramming is mainly concentrated on autosomes. We also found that the spatial binding ability of Oct4 binding can be represented quantitatively by using three parameters of peaks (height, width and distance). The dynamic changes of Oct4-binding demonstrated that the width play more important roles in regulating expression of target genes. At last, a multivariate linear regression was introduced to establish the spatial binding model of the Oct4-binding. The evaluation results confirmed that the height and width is positively correlated with the gene expression. And the additive interaction terms of height and width can better optimize the model performance than the multiplicative terms. The best average coefficients of determination of improved model achieved to 81.38%. Our study will provide new insights into the cooperative regulation of spatial binding pattern of pioneer factors in cell reprogramming.
了解先驱因子与其结合基因之间的靶向调控对于提高转录因子介导的重编程效率至关重要。Oct4作为唯一不能被其他POU成员替代的因子，迫切需要建立一个定量模型来描述其与靶基因的空间结合模式。先驱因子Oct4结合的动态图谱表明，主要峰值出现在细胞重编程的中期（第7天至第15天），且启动子是其优先靶向区域。Oct4的结合分布表现出明显的染色体偏向性。在1-11号染色体上的总体富集高于其他染色体。转录因子介导的重编程的显著事件主要集中在常染色体上。我们还发现，Oct4结合的空间结合能力可以通过峰的三个参数（高度、宽度和距离）进行定量表示。Oct4结合的动态变化表明，宽度在调节靶基因表达中起更重要的作用。最后，引入多元线性回归建立Oct4结合的空间结合模型。评估结果证实，高度和宽度与基因表达呈正相关。并且高度和宽度的加性相互作用项比乘性项能更好地优化模型性能。改进模型的最佳平均决定系数达到了81.38%。我们的研究将为细胞重编程中先驱因子空间结合模式的协同调控提供新的见解。
