Genome-wide binding potential and regulatory activity of the glucocorticoid receptor’s monomeric and dimeric forms

Thomas A. Johnson, Ville Paakinaho, Sohyoung Kim, Gordon L. Hager () and Diego M. Presman ()
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Thomas A. Johnson: Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH
Ville Paakinaho: Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH
Sohyoung Kim: Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH
Gordon L. Hager: Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH
Diego M. Presman: Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract A widely regarded model for glucocorticoid receptor (GR) action postulates that dimeric binding to DNA regulates unfavorable metabolic pathways while monomeric receptor binding promotes repressive gene responses related to its anti-inflammatory effects. This model has been built upon the characterization of the GRdim mutant, reported to be incapable of DNA binding and dimerization. Although quantitative live-cell imaging data shows GRdim as mostly dimeric, genomic studies based on recovery of enriched half-site response elements suggest monomeric engagement on DNA. Here, we perform genome-wide studies on GRdim and a constitutively monomeric mutant. Our results show that impairing dimerization affects binding even to open chromatin. We also find that GRdim does not exclusively bind half-response elements. Our results do not support a physiological role for monomeric GR and are consistent with a common mode of receptor binding via higher order structures that drives both the activating and repressive actions of glucocorticoids.

Date: 2021
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DOI: 10.1038/s41467-021-22234-9

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