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Cell. 2016 Aug 25;166(5):1269-1281.e19. doi: 10.1016/j.cell.2016.07.049.

Direct GR Binding Sites Potentiate Clusters of TF Binding across the Human Genome.

Author information

1
Department of Cell Biology, Duke University, Durham, NC 27708, USA; Center for Genomic & Computational Biology, Duke University, Durham, NC 27708, USA.
2
Center for Genomic & Computational Biology, Duke University, Durham, NC 27708, USA; University Program in Genetics & Genomics, Duke University, Durham, NC 27708, USA.
3
Center for Genomic & Computational Biology, Duke University, Durham, NC 27708, USA; Program in Computational Biology & Bioinformatics, Duke University, Durham, NC 27708, USA.
4
Center for Genomic & Computational Biology, Duke University, Durham, NC 27708, USA; Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, NC 27708, USA.
5
Center for Genomic & Computational Biology, Duke University, Durham, NC 27708, USA; Department of Biostatistics & Bioinformatics, Duke University, Durham, NC 27708, USA. Electronic address: tim.reddy@duke.edu.

Abstract

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.

PMID:
27565349
PMCID:
PMC5046229
DOI:
10.1016/j.cell.2016.07.049
[Indexed for MEDLINE]
Free PMC Article

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