Sequences flanking the core-binding site modulate glucocorticoid receptor structure and activity

Stefanie Schöne (1) , Marcel Jurk (1) , Mahdi Bagherpoor Helabad (2) , Iris Dror (3) , Isabelle Lebars (4) , Bruno Kieffer (4) , Petra Imhof (2) , Remo Rohs (3) , Martin Vingron (1) , Morgane Thomas-Chollier (5) , Sebastiaan H Meijsing (1)

1 MPIMG - Max Planck Institute for Molecular Genetics
2 FU - Free University of Berlin
3 USC - University of Southern California
4 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
5 IBENS - Institut de biologie de l'ENS Paris

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.

Domaines: Bio-Informatique, Biologie Systémique [q-bio.QM]

Stefanie Schöne, Marcel Jurk, Mahdi Bagherpoor Helabad, Iris Dror, Isabelle Lebars, et al.. Sequences flanking the core-binding site modulate glucocorticoid receptor structure and activity. Nature Communications, 2016, 7 (1), ⟨10.1038/ncomms12621⟩. ⟨hal-03352071⟩