Tethering not required: the glucocorticoid receptor binds directly to activator protein-1 recognition motifs to repress inflammatory genes

Nucleic Acids Res. 2017 Aug 21;45(14):8596-8608. doi: 10.1093/nar/gkx509.


The glucocorticoid receptor (GR) is a ligand-regulated transcription factor that controls the expression of extensive gene networks, driving both up- and down-regulation. GR utilizes multiple DNA-binding-dependent and -independent mechanisms to achieve context-specific transcriptional outcomes. The DNA-binding-independent mechanism involves tethering of GR to the pro-inflammatory transcription factor activator protein-1 (AP-1) through protein-protein interactions. This mechanism has served as the predominant model of GR-mediated transrepression of inflammatory genes. However, ChIP-seq data have consistently shown GR to occupy AP-1 response elements (TREs), even in the absence of AP-1. Therefore, the current model is insufficient to explain GR action at these sites. Here, we show that GR regulates a subset of inflammatory genes in a DNA-binding-dependent manner. Using structural biology and biochemical approaches, we show that GR binds directly to TREs via sequence-specific contacts to a GR-binding sequence (GBS) half-site found embedded within the TRE motif. Furthermore, we show that GR-mediated transrepression observed at TRE sites to be DNA-binding-dependent. This represents a paradigm shift in the field, showing that GR uses multiple mechanisms to suppress inflammatory gene expression. This work further expands our understanding of this complex multifaceted transcription factor.

MeSH terms

  • Base Sequence
  • Binding Sites / genetics
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • DNA / chemistry
  • DNA / genetics
  • DNA / metabolism
  • Gene Expression Regulation*
  • HEK293 Cells
  • Humans
  • Inflammation / genetics*
  • Models, Molecular
  • Mutation
  • Nucleic Acid Conformation
  • Protein Binding
  • Protein Structure, Tertiary
  • Receptors, Glucocorticoid / chemistry
  • Receptors, Glucocorticoid / genetics*
  • Receptors, Glucocorticoid / metabolism
  • Response Elements / genetics*
  • Transcription Factor AP-1 / chemistry
  • Transcription Factor AP-1 / genetics*
  • Transcription Factor AP-1 / metabolism


  • Receptors, Glucocorticoid
  • Transcription Factor AP-1
  • DNA