The genome sequence of enhancers in the same module showed substantial enrichment for sequence motifs67 associated with diverse transcription factors (Fig. S13a). We found 84 significantly enriched motifs in 101 modules (Extended Data 8), indicating that enhancer modules likely represent co-regulated sets, and proposing candidate upstream regulators for nearly half of all modules. Direct application of the same approach and thresholds to the putative regulatory regions annotated in each of the 111 reference epigenomes led to significant enrichment for only 10 enriched motifs in 15 reference epigenomes (Fig. S13b,c) of which 8 are blood samples, and focusing on the regions unique to each of the 17 tissue groups (Fig. 2b) only led to 19 enriched motifs in 10 tissue groups (Fig. S13d,e), emphasizing the importance of studying regulatory motif enrichments at the level of enhancer modules.
