These distinct cistromes are reflected in marked differences in transcriptional response to progestins. PR binding in the two cell lines is BAY 73-4506 mediated by highly similar PREs, suggesting a similar mode of DNA interaction, but key differences in cofactor binding site enrichment, particularly FOXA1, suggest that the expression levels of these cofactors have potential to determine cell-specific binding and ligand response. This first detailed genome-wide survey of PR genomic interaction has identified non-overlapping PR binding sites in immortalized normal and malignant breast cells; shown that PR interactions occurred distal to proximal promoters, supporting the view that PR effects are mediated over a longer distance than has previously been expected for direct cis-acting transcription factors; and demonstrated that transcriptional cofactors are important contributors to cell-specific PR activity. Most PR binding regions were located more than 10 kb from the TSS of regulated genes, with less than 35% of regulated genes in both cell lines having PR binding regions within 10 kb of the TSS, and less than 4% of regulated genes having binding regions within 1 kb of the TSS. In both breast cell types, binding was correlated with gene regulation, with most progestin-regulated genes having one or more PR binding regions within 50 kb, and genes increased by progestin being more likely to be associated with PR binding sites than genes that were decreased. These Screening Libraries findings are consistent with observations for other nuclear receptors in comparable experimental systems. Reddy et al identified 4392 glucocorticoid receptor binding sites by ChIP-seq in dexamethasone-treated A549 cells . Welboren et al identified between 7713 and 10205 estrogendependent ER binding sites, depending on the peak-calling algorithm used, in MCF-7 cells . Both ER and GR demonstrate a correlation between binding and gene regulation, and in line with the findings of this study, a relatively low proportion of promoter proximal binding is reported . The stronger correlation between binding and transcriptional upregulation than down-regulation has also been described for ER and GR . The number of PR binding sites discovered markedly exceeded the number of progestin-regulated transcriptional targets and many PR binding sites were not associated with active transcription, as only 20% of PR binding regions were associated with transcriptional regulation in each cell line. This has been found for other nuclear receptors . A number of potential explanations are proposed . Some binding events may regulate transcription at a level below the detection threshold of genomewide expression profiling. Moreover, a subset of binding sites may represent weaker associations or binding occurring in only a subset of cells such that transcriptional regulation does not occur at a significant level.