In response to hormone activation of the glucocorticoid receptor, GR responsive promoters move through a complex series of activity states, a phenomenon we term promoter progression. Genome-wide profiling of glucocorticoid receptor (GR) regulated loci reveals several classes of response, including genes that are transiently activated and genes that are transiently repressed. In contrast to the conventional paradigm of activation and repression, GR modulation of genome function is more appropriately considered as the programming of a large number of responsive gene loci for complex, time-dependent expression profiles.
These continuously varying response profiles could arise by a variety of mechanisms. We have discovered that nuclear receptors interact dynamically with regulatory elements in living cells3, and have proposed the hit and run hypothesis for receptor function1,2,4. Under this model, GR and associated coregulators exchange continuously and rapidly with regulatory sites on a time scale of seconds. Receptor and/or associated factors are subject to time dependent modifications that alter their activity states5. Thus, the constant sampling of regulatory sites intrinsic in the hit and run mechanism allows for a continuous evolution in promoter targeted events directed by the returning receptor complexes. These findings illustrate the complexity of the GR response and underscore the dynamic nature of hormone action throughout the eucaryotic genome.
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2. (2004). Biochim. Biophys. Acta 1677:46.
3. (2000). Science 287:1262.
4. (2004). Ann. N. Y. Acad. Sci. 1024:213.
5. (2006). Molecular Cell 22:669.