Glucocorticoid receptor DNA occupancy and transcriptional regulation across cell types

In response to glucocorticoids, the glucocorticoid receptor induces a cell type specific transcriptional program through both direct and indirect interactions with glucocorticoid response elements (GREs). The association between GREs and regulated genes is often unclear, because a GRE can be tens of thousands of base pairs from the gene it regulates. To help understand the mechanisms driving GR-DNA binding and transcription, we looked at the genome-wide binding and transcriptional response to glucocorticoids in three cell lines. Consistent with previous reports, we found that binding is more closely associated with upregulation than with downregulation. Interestingly, we found that GR binding regions (GRBRs) that contain a canonical GR motif, called a GR binding sequence (GBS), are better predictors of upregulation than those lacking a GBS, while the reverse is true of downregulation. To help understand the determinants of cell type specific binding, we compared the sequences of the GRBRs in the three different cell types and found that binding motifs for both the glucocorticoid receptor and for other transcription factors are overrepresented to different degrees in each cell type. The canonical GR motif is present in 66% of the U2OS sites, verses 14% of the Nalm6 sites; similarly, the AP-1 binding motif is present in 22% of A549 sites and 6% of Nalm6 sites. This difference in the sequence composition of binding sites suggests that the determinants of binding may be encompassed in the local sequence of a binding site. Supporting this, we found that the cell type specificity of binding could be recapitulated in reporters containing approximately 400 base pairs of DNA