Sequences flanking the core-binding site modulate glucocorticoid receptor structure and activity.
Fiche publication
Date publication
septembre 2016
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr KIEFFER Bruno
Tous les auteurs :
Schöne S, Jurk M, Helabad MB, Dror I, Lebars I, Kieffer B, Imhof P, Rohs R, Vingron M, Thomas-Chollier M, Meijsing SH
Lien Pubmed
Résumé
The glucocorticoid receptor (GR) binds as a homodimer to genomic response elements, which have particular sequence and shape characteristics. Here we show that the nucleotides directly flanking the core-binding site, differ depending on the strength of GR-dependent activation of nearby genes. Our study indicates that these flanking nucleotides change the three-dimensional structure of the DNA-binding site, the DNA-binding domain of GR and the quaternary structure of the dimeric complex. Functional studies in a defined genomic context show that sequence-induced changes in GR activity cannot be explained by differences in GR occupancy. Rather, mutating the dimerization interface mitigates DNA-induced changes in both activity and structure, arguing for a role of DNA-induced structural changes in modulating GR activity. Together, our study shows that DNA sequence identity of genomic binding sites modulates GR activity downstream of binding, which may play a role in achieving regulatory specificity towards individual target genes.
Référence
Nat Commun. 2016 Sep;7:12621