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Genomic binding of transcription factors, like the glucocorticoid receptor (GR), is linked to the regulation of genes. However, as we show here, GR binding is a poor predictor of GR-dependent gene regulation even when taking the 3D organization of the genome into account. To connect GR binding sites to the regulation of genes in the endogenous genomic context, we turned to genome editing. By deleting GR binding sites, individually or in combination, we uncovered how cooperative interactions between binding sites contribute to the regulation of genes. Specifically, for the GR target gene GILZ, we show that the simultaneous presence of a cluster of GR binding sites is required for the activity of an individual enhancer and that the GR-dependent regulation of GILZ depends on multiple GR-bound enhancers. Further, by deleting GR binding sites that are shared between different cell types, we show how cell type-specific genome organization and enhancer-blocking can result in cell type-specific wiring of promoter–enhancer contacts. This rewiring allows an individual GR binding site shared between different cell types to direct the expression of distinct transcripts and thereby contributes to the cell type-specific consequences of glucocorticoid signaling.

Genomic dissection of enhancers uncovers principles of combinatorial regulation and cell type-specific wiring of enhancer–promoter contacts