Insights into Negative Regulation by the Glucocorticoid Receptor from Genome-wide Profiling of Inflammatory Cistromes

N. Henriette Uhlenhaut, Grant D. Barish, Ruth T. Yu, Michael Downes, Malith Karunasiri, Christopher Liddle, Petra Schwalie, Norbert Hübner, Ronald M. Evans*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

154 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)158-171
Number of pages14
JournalMolecular cell
Volume49
Issue number1
DOIs
StatePublished - Jan 10 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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