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Genome Biol. 2014 Jul 31;15(8):418. [Epub ahead of print]

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 GR¿ in binding and regulation of target genes. Genomic regions strongly occupied by A477T are enriched for a novel half site motif. In vitro, GR¿ binds half sites as a monomer. Through the overlap between GR¿- and A477T-bound regions, we identify GR¿-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.

PMID:
25085117
[PubMed - as supplied by publisher]
PMCID:
PMC4149261
Free PMC Article

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