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Mol Cell. 2013 Jan 10;49(1):158-71. doi: 10.1016/j.molcel.2012.10.013. Epub 2012 Nov 15.

Insights into negative regulation by the glucocorticoid receptor from genome-wide profiling of inflammatory cistromes.

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1
Gene Expression Laboratory, Howard Hughes Medical Institute, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Abstract

How the glucocorticoid receptor (GR) activates some genes while potently repressing others remains an open question. There are three current models for suppression: transrepression via GR tethering to AP-1/NF-κB sites, direct GR association with inhibitory elements (nGREs), and GR recruitment of the corepressor GRIP1. To gain insights into GR suppression, we used genomic analyses and genome-wide profiling of GR, p65, and c-Jun in LPS-stimulated macrophages. We show that GR mediates both activation and repression at tethered sites, GREs, and GRIP1-bound elements, indicating that motif classification is insufficient to predict regulatory polarity of GR binding. Interestingly, sites of GR repression utilize GRIP1's corepressor function and display reduced histone acetylation. Together, these findings suggest that while GR occupancy confers hormone responsiveness, the receptor itself may not participate in the regulatory effects. Furthermore, transcriptional outcome is not established by sequence but is influenced by epigenetic regulators, context, and other unrecognized regulatory determinants.

PMID:
23159735
PMCID:
PMC3640846
DOI:
10.1016/j.molcel.2012.10.013
[Indexed for MEDLINE]
Free PMC Article

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