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

Schöne, S.; Jurk, M.; Helabad, M. B.; Dror, I.; Lebars, I.; Kieffer, B.; Imhof, P.; Rohs, R.; Vingron, M.; Thomas-Chollier, M.; Meijsing, S.

doi:10.1038/ncomms12621

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

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Schöne, S.
Mechanisms of Transcriptional Regulation (Sebastiaan H. Meijsing), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Jurk, M.
Mechanisms of Transcriptional Regulation (Sebastiaan H. Meijsing), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Vingron, M.
Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Meijsing, S.
Mechanisms of Transcriptional Regulation (Sebastiaan H. Meijsing), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Schöne, S., Jurk, M., Helabad, M. B., Dror, I., Lebars, I., Kieffer, B., et al. (2016). Sequences flanking the core-binding site modulate glucocorticoid receptor structure and activity. Nature Communications, 7: 12621. doi:10.1038/ncomms12621.

Cite as: https://hdl.handle.net/11858/00-001M-0000-002D-44F9-A

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.