Chromatin Remodeling Proteins

Division Of Basic Sciences - Nci

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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, allegedly incapable of DNA binding and dimerization. Although quantitative live-cell imaging data shows GRdim as mostly dimeric, genomic studies, on the basis of recovery of enriched half-site response elements, suggest monomeric engagement on DNA. We performed genome-wide studies on GRdim and a constitutive monomeric mutant. The results show that GR must form dimers to bind even pre-accessible chromatin and that earlier characterization of half-response elements do not constitute solid evidence of monomeric action. Theses results undermine any physiological role of 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.