We next sought to distinguish likely activator and repressor motifs, by identifying regulators whose expression pattern across cell/tissue types shows a strong (positive or negative) correlation with the activity of enhancers in the enriched module9. We focused on the 40 most strongly expression-correlated regulators (Extended Data 9a), and used the module-level motif enrichments to link each regulator to the cell/tissue types that define each module (Fig. 8). We found that many of the inferred links correspond to known regulatory relationships, including: OCT4 (also known as POU5F1) in pluripotent cells, HNF1B and HNF4A1 in liver and other digestive tissues, RFX4 in neurosphere and neuronal cells, and MEF2D in muscle. The most enriched regulators showed primarily positive correlations, suggesting they function as transcriptional activators, while a subset of factors showed a negative correlation, with the factor expressed in the lineages where its motif showed enhancer depletion, suggesting a repressive role. For example, REST (also known as NRSF), a known repressor of neuronal lineages was least expressed in neuronal tissues, where its motif was most enriched in enhancers, and a similar signature was found for ZBTB1B, a known repressor of myogenesis and brain development.
