TY - JOUR
T1 - Insights into Negative Regulation by the Glucocorticoid Receptor from Genome-wide Profiling of Inflammatory Cistromes
AU - Uhlenhaut, N. Henriette
AU - Barish, Grant D.
AU - Yu, Ruth T.
AU - Downes, Michael
AU - Karunasiri, Malith
AU - Liddle, Christopher
AU - Schwalie, Petra
AU - Hübner, Norbert
AU - Evans, Ronald M.
N1 - Funding Information:
We thank E. Ong, S. Ganley, and C. Brondos for administrative assistance; J. Nery for DNA sequencing; C. Benner for assistance with HOMER software; and H. Juguilon, M. Heinig, and A. Bauerfeind for technical assistance. N.H.U. was supported by an EMBO fellowship (EMBO ALTF 686-2010) and G.D.B. by K08HL092298. This work was funded by grants from the National Institutes of Health (HL105278, HL088093, DK057978, DK090962, CA014195, and ES010337), the Helmsley Charitable Trust, and the Samuel Waxman Cancer Research Foundation. R.M.E. is an investigator of the Howard Hughes Medical Institute and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute.
PY - 2013/1/10
Y1 - 2013/1/10
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2012.10.013
DO - 10.1016/j.molcel.2012.10.013
M3 - Article
C2 - 23159735
AN - SCOPUS:84872263381
SN - 1097-2765
VL - 49
SP - 158
EP - 171
JO - Molecular Cell
JF - Molecular Cell
IS - 1
ER -