Glucocorticoid receptor binds half sites as a monomer and regulates specific target genes

Abstract

BackgroundGlucocorticoid receptor (GR) is a hormone-activated, DNA-binding transcriptional regulatory factor that controls inflammation, metabolism, stress responses, and other physiological processes. In vitro, GR binds as an inverted dimer to a motif consisting of two imperfectly palindromic 6 bp half sites separated by 3 bp spacers. In vivo, GR employs different patterns of functional surfaces of GR to regulate different target genes. The relationships between GR genomic binding and functional surface utilization have not been defined.ResultsWe find that A477T, a GR mutant that disrupts the dimerization interface, differs from wild-type GRα in binding and regulation of target genes. Genomic regions strongly occupied by A477T are enriched for a novel half site motif. In vitro, GRα binds half sites as a monomer. Through the overlap between GRα- and A477T-bound regions, we identify GRα-bound regions containing only half sites. We further identify GR target genes linked with half sites and not with the full motif.ConclusionsGenomic regions bound by GR differ in underlying DNA sequence motifs and in the GR functional surfaces employed for regulation. Identification of GR binding regions that selectively utilize particular GR surfaces may discriminate sub-motifs, including the half site motif, that favor those surfaces. This approach may contribute to predictive models for GR activity and therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0418-y) contains supplementary material, which is available to authorized users.

TNF-α inhibits glucocorticoid receptor-induced gene expression by reshaping the GR nuclear cofactor profile

“…These GRE sequences form variations of a 15-bp consensus sequence consisting of two imperfect palindromic hexamers separated by a 3-bp spacer (5). GR monomers are also able to bind DNA directly, on half GRE sites (6), and can also regulate expression of certain genes in a direct way, but GR homodimer ization has appeared as the dominant GR configuration leading to direct gene regulation by GR. Many of these insights have followed from studies using the GRdim mutant mice, which express a poorly dimer-forming GR (7) and by recent genome-wide ChIP studies (6).…”

“…GR monomers are also able to bind DNA directly, on half GRE sites (6), and can also regulate expression of certain genes in a direct way, but GR homodimer ization has appeared as the dominant GR configuration leading to direct gene regulation by GR. Many of these insights have followed from studies using the GRdim mutant mice, which express a poorly dimer-forming GR (7) and by recent genome-wide ChIP studies (6). Genes that are controlled by direct GR gene regulation include antiinflammatory genes, such as Dusp1 (encoding MKP-1) and Tsc22d3 (encoding GILZ) (5).…”

The Glucocorticoid Receptor (GR) Stimulates Herpes Simplex Virus 1 Productive Infection, in Part Because the Infected Cell Protein 0 (ICP0) Promoter Is Cooperatively Transactivated by the GR and Krüppel-Like Transcription Factor 15

“…4B). A GR monomer can bind certain half-GREs, leading to promoter activation, and most contain the ACA core (24) (Fig. 4B).…”

Comparing the rules of engagement of androgen and glucocorticoid receptors

“…2 a Logo presentation of top-enriched ARE motifs provided by Cheung based on [99] ( top ) and top-enriched GRE motifs from [35] ( bottom ). b Logo presentation of top-enriched ARE motifs specific for the SPARKI model, considered to be selAREs ( top ) or for classical AREs ( bottom ).Adapted from [48] …”