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

• Type of Material: Article
• Authors: Emily R. Weikum, Emory University; Ian Mitchelle S. de Vera, Scripps Research Institute; Jerome C. Nwachukwu, Scripps Research Institute; William Hudson, Emory University; Kendall W. Nettles, Scripps Research Institute; Douglas J. Kojetin, Scripps Research Institute; Eric Ortlund, Emory University
• Language: English
• Date: 2017-08-21
• Publisher: Oxford University Press (OUP): Policy C - Option B
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1093/nar/gkx509
• Title of Journal or Parent Work: Nucleic Acids Research
• ISSN: 0305-1048
• Volume: 45
• Issue: 14
• Start Page: 8596
• End Page: 8608
• Grant/Funding Information: J.C.N is supported by the BallenIsles Men's Golf Association.; National Institutes of Health General Medical Sciences [1F31GM113397-01A1 to E.R.W.]; National Institutes of Health [R01DK095750 to E.A.O.]; AHA [14GRNT20460124 to E.A.O.]; W.M. Keck Foundation Medical Research Grant (to E.A.O.); National Institutes of Health [R01DK101871 to D.J.K.]; National Institutes of Health [R01GM114420 to D.J.K.].; Funding for open access charge: W.M. Keck Foundation Grant.
• Keywords: TRANSCRIPTION FACTORS; KAPPA-B; FUNCTIONAL ANTAGONISM; Life Sciences & Biomedicine; CHROMATIN ACCESSIBILITY; C-JUN; Science & Technology; MOLECULAR-MECHANISMS; TYROSINE-HYDROXYLASE GENE; COMPOSITE RESPONSE ELEMENT; Biochemistry & Molecular Biology; DNA-BINDING; ANTIINFLAMMATORY ACTION
• Research Categories: Chemistry, Biochemistry; Biology, Genetics

Abstract

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.