Numerous studies of relationship between epigenomic features have focused on their strong correlation across the genome, likely because such relationship can be easily identified by many established methods for correlation analysis. However, two features with little correlation may still colocalize at many genomic sites to implement important functions. There is no bioinformatic tool for researchers to specifically identify such feature pairs. Here, we develop a method to identify feature pairs in which two features have maximal colocalization minimal correlation (MACMIC) across the genome. By MACMIC analysis of 3306 feature pairs in 16 human cell types, we reveal a dual role of CCCTC-binding factor (CTCF) in epigenetic regulation of cell identity genes. Although super-enhancers are associated with activation of target genes, only a subset of super-enhancers colocalized with CTCF regulate cell identity genes. At super-enhancers colocalized with CTCF, CTCF is required for the active marker H3K27ac in cell types requiring the activation, and also required for the repressive marker H3K27me3 in other cell types requiring repression. Our work demonstrates the biological utility of the MACMIC analysis and reveals a key role for CTCF in epigenetic regulation of cell identity. The code for MACMIC is available at https://github.com/bxia888/MACMIC.

许多表观基因组特征之间关系的研究都集中在它们在整个基因组中的强相关性上，这可能是因为这种关系可以通过许多已建立的相关分析方法轻松识别。然而，相关性不大的两个特征仍可能共定位于许多基因组位点以实现重要功能。目前还没有生物信息学工具可供研究人员专门识别此类特征对。在这里，我们开发了一种识别特征对的方法，其中两个特征在整个基因组中具有最大共定位最小相关性（MACMIC）。通过对 16 种人类细胞类型的 3306 个特征对进行 MACMIC 分析，我们揭示了CCCTC 结合因子的双重作用（CTCF）在细胞身份基因的表观遗传调控中。尽管超级增强子与靶基因的激活相关，但只有一部分超级增强子与 CTCF 共定位，调节细胞身份基因。在与 CTCF 共定位的超级增强子中，CTCF 是需要激活的细胞类型中的活性标记H3K27ac所必需的，也是需要抑制的其他细胞类型中的抑制标记H3K27me3所必需的。我们的工作展示了 MACMIC 分析的生物学效用，并揭示了 CTCF 在细胞身份表观遗传调控中的关键作用。MACMIC 的代码可在 https://github.com/bxia888/MACMIC 获取。