We next studied the impact of primary DNA sequence on the epigenomic landscape, across genomic regions and between the two alleles of a given individual. First, we evaluated whether histone modifications and DNA methylation can be predicted by the underlying DNA sequence using DNA motifs for TFs expressed in ESCs and four ES-derived cell types. Using the area under the receiver operating curve (AUROC), we found between 71% predictive power for H3K4me1 peaks and 98% for H3K4me3 peaks (average of 85% across six marks and methylation-depleted regions)70. The most predictive motifs were those of factors associated with specific histone modifications or specific cell-types, and were found within peak regions enriched for chromatin marks and at their boundaries. As an example of a boundary enrichment, H3K4me3 peaks were flanked by motifs consisting of a continuous stretch of A and T followed by a G and C cap, which may play a role in nucleosome positioning or recruiting promoter-associated TFs, such as nuclear receptors. Enhancer and promoter-predictive motifs were enriched in high-resolution DNase hypersensitive sites (Table S5a), suggesting they correspond to TF-bound sequences.
