Glucocorticoid receptor-promoter interactions: Energetic dissection suggests a framework for the specificity of steroid receptor-mediated gene regulation

摘要

The glucocorticoid receptor (GR) is a member of the steroid receptor family of ligand-activated transcription factors. A number of studies have shown that steroid receptors regulate distinct but overlapping sets of genes; however, the molecular basis for such specificity remains unclear. Previous work from our laboratory has demonstrated that under identical solution conditions, three other steroid receptors [the progesterone receptor A isoform (PR-A), the progesterone receptor B isoform (PR-B), and estrogen receptor α (ER-α)] differentially partition their self-association and promoter binding energetics. For example, PR-A and PR-B generate similar dimerization free energies but differ significantly in their extents of intersite cooperativity. Conversely, ER-α maintains an intersite cooperativity most comparable to that of PR-A yet dimerizes with an affinity orders of magnitude greater than that of either of the PR isoforms. We have speculated that these differences serve to generate receptor-specific promoter occupancies, and thus receptor-specific gene regulation. Noting that GR regulates a unique subset of genes relative to the other receptors, we hypothesized that the receptor should maintain a unique set of interaction energetics. We rigorously determined the self-association and promoter binding energetics of full-length, human GR under conditions identical to those used in our earlier studies. We find that unlike all other receptors, GR shows no evidence of reversible self-association. Moreover, GR assembles with strong intersite cooperativity comparable to that seen only for PR-B. Finally, simulations show that such partitioning of interaction energetics allows for receptor-specific promoter occupancies, even under conditions where multiple receptors are competing for binding at identical sites. (Graph Presented).