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.
由于关联性分析可以很好的发现具有相关性的特征组合，因此表观基因组学特征的关联性研究主要集中在对于强相关的特征组合的研究。然而，除了强相关特征组合外，两个低相关性的表观基因组学特征同样可能共存于基因组的很多位置，这类特征组合同样可以有重要的生物学功能。目前没有生物信息学方法可以有效的发现这类特征组合。我们开发了MACMIC算法，MACMIC可以用于鉴定低相关性、高共定位的表观基因组学特征组合。我们将MACMIC用于15个细胞类别中的3385个特征对，发现了CCCTC-binding factor（CTCF）在表观基因组学中的双重调控功能。已有的研究发现超级增强子主要调控细胞身份基因（cell identity gene），本研究发现只有与CTCF共定位的超级增强子是主要调控细胞身份基因（Cell identity gene）。在对超级增强子与CTCF共定位的区域的进一步研究中，我们发现在需要该区域被激活的细胞中CTCF在DNA上的结合是对应的染色体位置上获得H3K27ac修饰的必要条件，在需要该区域被抑制的细胞中CTCF的结合是获得H3K27me3修饰的必要条件。我们的工作显示出MACMIC在生物学中广泛的应用前景，同时发现CTCF可以从表冠基因组层面调控细胞身份基因。MACMIC的脚本可以从GitHub网站中下载，https://github.com/bxia888/MACMIC。





PDF全文下载地址:

http://gpb.big.ac.cn/articles/download/842