TF-binding regions are non-randomly distributed across the genome, with respect to both other features (e.g., promoters) and other TF-binding regions. Within the Tier 1 and 2 cell lines, we found 3,307 pairs of statistically co-associated factors (P value < 1E-16, GSC) involving 114 out of a possible 117 factors (97%) (Figure 4A). These include expected associations, such as Jun and Fos, and some more novel associations, such as TCF7L2 with HNF4alpha and FoxA267 (a full listing is given in Supplementary Table F1). When one considers promoter and intergenic regions separately, this changes to 3,201 pairs (116 factors, 99%) for promoters and 1,564 pairs (108 factors, 92%) for intergenic regions, with some associations more specific to these genomic contexts (e.g., the cluster of HDAC2, GABPA, CHD2, GTF2F1, MXI1, and MYC in promoter regions and SP1, EP300, HDAC2, and NANOG in intergenic regions (Figure 4B)). These general and context-dependent associations lead to a network representation of the co-binding with many interesting properties, explored in refs 19,25,26. In addition we also identified a set of regions bound by multiple factors representing “High Occupancy of TFs” (HOT) regions68.
