De novo motif discovery in enhancer footprint sequences reveals novel binding patterns of well-characterized TFs. Motifs of known activators in the HUVEC, K562, HSMM, and HepG2 cell lines can co-occur together. For example, in the HUVEC enhancer footprint sequences, the ERG motif, a member of the ETS family that is characterized by a “GGAA” binding paper, often co-occurs with the AP-1 motif. In the presence of the AP-1 motif, the degree of resemblance of a predicted site to the ERG motif is weaker. SPI1, another member of the ETS family, shares a similar relationship with the GATA1 motif in K562. In other examples, activator TFs appear to often homodimerize and form palindromic motifs. Sequence logos of examples of de novo motifs in the cell types are displayed alongside, if available, CentriMo E-values and number of matches in SE DHS sequences (“Methods”). For two of the HepG2 examples, the motifs are so infrequent that CentriMo failed to find a significant number of matches in SE sequences.