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

Stefanie Schöne, Marcel Jurk, Mahdi Bagherpoor Helabad, Iris Dror, Isabelle Lebars, Bruno Kieffer, Petra Imhof, Remo Rohs, Martin Vingron, Morgane Thomas-Chollier () and Sebastiaan H. Meijsing ()
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Stefanie Schöne: Max Planck Institute for Molecular Genetics
Marcel Jurk: Max Planck Institute for Molecular Genetics
Mahdi Bagherpoor Helabad: Institute of Theoretical Physics, Free University Berlin
Iris Dror: Molecular and Computational Biology Program, University of Southern California
Isabelle Lebars: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS) UMR 7104/Institute National de la Santé et de la Recherche Médicale (INSERM) U964/Université de Strasbourg, 1 rue Laurent Fries
Bruno Kieffer: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS) UMR 7104/Institute National de la Santé et de la Recherche Médicale (INSERM) U964/Université de Strasbourg, 1 rue Laurent Fries
Petra Imhof: Institute of Theoretical Physics, Free University Berlin
Remo Rohs: Molecular and Computational Biology Program, University of Southern California
Martin Vingron: Max Planck Institute for Molecular Genetics
Morgane Thomas-Chollier: Institut de Biologie de l'Ecole Normale Supérieure, Institut National de la Santé et de la Recherche Médicale, U1024, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8197
Sebastiaan H. Meijsing: Max Planck Institute for Molecular Genetics

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms12621

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