TF binding sites provide a natural focus around which to explore chromatin properties. TFs are often multi-functional and can bind a variety of genomic loci with different combinations and patterns of chromatin marks and nucleosome organization. Hence, rather than averaging chromatin mark profiles across all binding sites of a TF, we developed a clustering procedure, termed the Clustered Aggregation Tool (CAGT), to identify subsets of binding sites sharing similar but distinct patterns of chromatin mark signal magnitude, shape, and hidden directionality 30. For example, the average profile of the repressive histone mark, H3K27me3, over all 55,782 CTCF-binding sites in K562 shows poor signal enrichment (Figure 3A). However, after grouping profiles by signal magnitude, we found a subset of 9,840 (17.6%) CTCF-binding sites that exhibit significant flanking H3K27me3 signal. Shape and orientation analysis further revealed that the predominant signal profile for H3K27me3 around CTCF peak summits is asymmetric, consistent with a boundary role for some CTCF sites between active and polycomb-silenced domains. Further examples are provided in Supplementary Figures E5 and E6. For TAF1, predominantly found near TSSs, the asymmetric sites
