title: Ligand-induced repression of the glucocorticoid receptor gene is mediated by an NCoR1 repression complex formed by long-range chromatin interactions with intragenic glucocorticoid response elements.
abstract: Glucocorticoids are among the most potent and effective agents for treating inflammatory diseases and hematological cancers. However, subpopulations of patients are often resistant to steroid therapy, and determining the molecular mechanisms that contribute to glucocorticoid resistance is thus critical to addressing this clinical problem affecting patients with chronic inflammatory disorders. Since the cellular level of the glucocorticoid receptor (GR) is a critical determinant of glucocorticoid sensitivity and resistance, we investigated the molecular mechanisms mediating repression of glucocorticoid receptor gene expression. We show here that glucocorticoid-induced repression of GR gene expression is mediated by inhibition of transcription initiation. This process is orchestrated by the recruitment of agonist-bound GR to exon 6, followed by the assembly of a GR-NCoR1-histone deacetylase 3-containing repression complex at the transcriptional start site of the GR gene. A functional negative glucocorticoid response element (nGRE) in exon 6 of the GR gene and a long-range interaction occurring between this intragenic response element and the transcription start site appear to be instrumental in this repression. This autoregulatory mechanism of repression implies that the GR concentration can coordinate repression with excess ligand, regardless of the combinatorial associations of tissue-specific transcription factors. Consequently, the chronic nature of inflammatory conditions involving long-term glucocorticoid administration may lead to constitutive repression of GR gene transcription and thus to glucocorticoid resistance.
authors: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina, USA.
authors: Sivapriya
authors: S
authors: Ramamoorthy
authors: John A
authors: JA
authors: Cidlowski
mesh_terms: D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D004351:Drug Resistance; D005091:Exons / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D056971:Nuclear Receptor Co-Repressor 1 / Q000378:metabolism*; D051381:Rats; D011965:Receptors, Glucocorticoid / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects*; D015533:Transcriptional Activation / Q000187:drug effects; D000099186:Histone Deacetylase 3
chemical_list: D002843:Chromatin; D005938:Glucocorticoids; D006655:Histone Deacetylases; D008024:Ligands; D056971:Nuclear Receptor Co-Repressor 1; D011965:Receptors, Glucocorticoid; D000099186:Histone Deacetylase 3; C539127:NCOR1 protein, human