Biased Agonism Mediated by the Glucocorticoid Receptor

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Background****Glucocorticoids are a family of naturally-occurring and synthetic agonists, which regulate the expression of genes controlling a wide variety of physiological functions including metabolism, development, inflammation and the immune system. These genomic effects are mediated by the glucocorticoid receptor (GR), a ligand-activated transcription factor, which is a member of the nuclear hormone receptor (NHR) superfamily.******Current concepts of GR-mediated gene expression assume that GR adopts the same, static conformation when bound by an activating ligand (i.e. agonist). Accordingly, the magnitude of gene expression changes is governed by the transcriptional competency of the ligand-receptor complex, which is determined by the innate chemical structure of the agonist. However, structural biologists have unequivocally established that GR can adopt multiple, interchangeable conformations, which are differentially stabilized in an agonist-dependent manner. Borrowing from the literature on 7-transmembrane spanning receptors, this plasticity may allow GR to interact, preferentially, with one gene promoter (or population of promoters) over another leading to distinct, agonist-directed programs of gene expression by a process called biased agonism.*******Hypothesis****The overall hypothesis is that distinct programs of GR-mediated gene expression can be generated in a given cell type that depend on the innate structure of an activating ligand and its ability to create unique conformations of GR. This changes the complement and stoichiometry of obligatory co-factors that bind to GR and, thereby, its ability to interact productively at certain gene promoters over others.*******Aims**** • To conduct a "proof-of-concept" study to establish GR-mediated gene expression bias;*** • To validate, quantify and analyse, using bioinformatics approaches, gene expression bias;*** • To explore in vitro the biological activity of biased GR agonists.******Anticipated Outcomes and Discovery Potential****This programme of research will apply biological, analytical and bioinformatics approaches, to establish a fundamental biological process of GR-mediated gene expression whereby distinct, transcriptional signatures are directed by the innate structure of an activating ligand. Many ligands have been identified with the potential to stabilise GR in distinct conformations and direct different patterns of gene expression through biased agonism. A ligand, by creating a unique, GR conformer, should be able to "program" a cell to preferentially express distinct populations of genes with attendant functional consequences. Establishing the principle of GR-mediated, biased agonism could be extrapolated to other NHRs, apply across species and be relevant to all biologists interested in the regulation of gene expression. ********