Transcription factors (TFs) regulate gene expression by binding to specific DNA sites in cis regulatory regions of genes. Most eukaryotic TFs are members of protein families that share a common DNA binding domain and often recognize highly similar DNA sequences. Currently, it is not well understood why closely related TFs are able to bind different genomic regions
, despite having the potential to interact with the same DNA sites. Here, we use the Myc/Max/Mad family as a model system to investigate whether interactions with additional proteins (co-factors) can explain why paralogous TFs with highly similar DNA binding preferences interact with different genomic sites
. We use a classification approach to distinguish between targets of c-Myc versus Mad2, using features that reflect the DNA binding specificities of putative co-factors. When applied to c-Myc/Mad2 DNA binding data, our algorithm can distinguish between genomic regions bound uniquely by c-Myc versus Mad2 with 87% accuracy.