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Direct GR Binding Sites Potentiate Clusters of TF Binding across the Human Genome
Ist Teil von
Cell, 2016-08, Vol.166 (5), p.1269-1281.e19
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2016
Link zum Volltext
Quelle
EZB Electronic Journals Library
Beschreibungen/Notizen
The glucocorticoid receptor (GR) binds the human genome at >10,000 sites but only regulates the expression of hundreds of genes. To determine the functional effect of each site, we measured the glucocorticoid (GC) responsive activity of nearly all GR binding sites (GBSs) captured using chromatin immunoprecipitation (ChIP) in A549 cells. 13% of GBSs assayed had GC-induced activity. The responsive sites were defined by direct GR binding via a GC response element (GRE) and exclusively increased reporter-gene expression. Meanwhile, most GBSs lacked GC-induced reporter activity. The non-responsive sites had epigenetic features of steady-state enhancers and clustered around direct GBSs. Together, our data support a model in which clusters of GBSs observed with ChIP-seq reflect interactions between direct and tethered GBSs over tens of kilobases. We further show that those interactions can synergistically modulate the activity of direct GBSs and may therefore play a major role in driving gene activation in response to GCs.
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•Direct glucocorticoid (GC) receptor binding sites (GBSs) encode GC-induced enhancers•Non-GC-induced GBSs cluster around and interact with direct GBSs•These interactions amplify the activity of directly bound GC-inducible enhancers•This enhancer-cluster mechanism of regulation is general to the estrogen receptor
Transcription factor binding across the genome is not a series of independent events but instead results from interactions between distal sites that dramatically alter their regulatory activity.