GSE168767
Glucocorticoid receptor collaborates with pioneer factors and AP-1 to execute genome-wide regulation
The glucocorticoid receptor (GR) regulates transcription through binding to specific DNA motifs, particularly at enhancers. While the motif to which it binds is constant across cell types, GR has cell-type specific binding at genomic loci, resulting in expression of different genes. The presence of other bound transcription factors (TFs) is hypothesized to specify where GR binds. Here, we addressed the roles of other TFs in the glucocorticoid response by comparing changes in GR binding and nascent transcription at candidate cis-regulatory elements in two distinct cell types. We found that each cell type binds GR at thousands of non-overlapping loci, but only a small fraction of these sites also show changes in transcription. GR binding is associated with pioneer factor binding, whereas transcription is induced at sites bound by AP-1. These results support a model of transcriptional regulation in which multiple classes of TFs are required. The pioneer factors increase chromatin accessibility, facilitating the binding of GR and additional factors. AP-1 then poises a fraction of sites to be rapidly activated upon glucocorticoid-induced GR binding. GR also induces transcription at a specific set of enhancers. The coordinated activity of multiple TFs then results in cell-type specific changes in gene expression. We anticipate that many models of inducible gene expression also require multiple distinct TFs that act at multiple rate-limited steps of transcriptional regulation. Overall design: Nascent transcription in cells with different dexamethasone treatments.