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

Official URL:https://doi.org/10.1016/j.molcel.2012.10.013
PubMed:View item in PubMed
Creators Name:Uhlenhaut, N.H. and Barish, G.D. and Yu, R.T. and Downes, M. and Karunasiri, M. and Liddle, C. and Schwalie, P. and Huebner, N. and Evans, R.M.
Journal Title:Molecular Cell
Journal Abbreviation:Mol Cell
Volume:49
Number:1
Page Range:158-171
Date:10 January 2013
Keywords:Acetylation, Amino Acid Sequence, Base Sequence, Binding Sites, Chromosome Mapping, Cluster Analysis, Consensus Sequence, Cultured Cells, Dexamethasone, Genetic Epigenesis, Genome, Glucocorticoids, Glucocorticoid Receptors, Histones, Inbred C57BL Mice, Inflammation, Interferon Regulatory Factor-3, Lipopolysaccharides, Macrophages, Molecular Sequence Data, Nerve Tissue Proteins, Post-Translational Protein Processing, Protein Binding, Response Elements, Signal Transducing Adaptor Proteins, Transcription Factors, Transcriptome, Animals, Mice
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-{kappa}B 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.
ISSN:1097-2765
Publisher:Cell Press (U.S.A.)
Item Type:Article

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