Differential nuclear localisation and promoter occupancy play a role in glucocorticoid receptor ligand-specific transcriptional responses.

Hadley KE, Louw A, Hapgood JP

The glucocorticoid receptor (GR) is a ligand-activated transcription factor for which a number of endogenous and synthetic ligands exist. A key question in steroid receptor biology is how different ligands elicit different maximal transcriptional responses via the same receptor and on the same promoter. This question was addressed quantitatively for the GR, using a panel of agonists, partial agonists and antagonists, on the endogenous GILZ gene in two different human cell lines. It was found that the extent of GR nuclear localization correlated with the efficacy for GILZ transactivation by the GR in U2OS cells. However, in A549 cells there was no significant correlation, with all ligands resulting in similar levels of GR nuclear localization, despite different levels of transcriptional activation of the GILZ gene. Chromatin immunoprecipitation analysis on the other hand, revealed ligand-specific differences in GILZ promoter occupancy in the A549 cells, which correlated with the transcriptional efficacy of the subset of ligands investigated. This suggests that ligand-specific differences in promoter occupancy by activated GR play a major role in discrimination between agonist, partial agonist and antagonist responses on the endogenous GILZ gene in A549 cells, while differences in nuclear localisation of liganded GR play a role in determining the transcriptional outcome in U2OS cells. These cell line-specific differences were not dependent on the amount of GR present, since transient overexpression of GR in U2OS did not alter the relative ligand-selective nuclear localisation. Our results show that there is a relationship between ligand-specific transactivation efficacy, extent of nuclear translocation and recruitment of GR to the promoter. However, the relative contribution of nuclear translocation and GR promoter recruitment to ligand-specific transactivation efficacy is cell-specific.

Chromatin Shearing

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May, 2011



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