Direct GR Binding Sites Potentiate Clusters of TF Binding across the Human Genome
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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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MPRAs have been applied to assess biochemically annotated candidate enhancers, candidate enhancers harbouring variants that potentially mediate eQTLs, and even scans of the entire human genome.
“MPRAs have been applied to assess biochemically annotated candidate enhancers77,176-178, candidate enhancers harbouring variants that potentially mediate eQTLs179-182, and even scans of the entire human genome108,183.”
From Towards a comprehensive catalogue of validated and target-linked human enhancers (2020) · cites this paper as [176]
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- Authors
- Vockley, C. M., D’Ippolito, A. M., McDowell, I. C., Majoros, W. H., Safi, A., Song, L., Crawford, G. E., & Reddy, T. E.
- Affiliations
- Duke University (US)
- Corresponding author
- Reddy, Timothy E.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 166
- Issue
- 5
- Pages
- 1269-1281.e19
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5046229
- OpenAlex
- W2515307706
- Cited by
- 182
- References
- 69
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 12 · 2023: 13 · 2022: 19 · 2021: 24 · 2020: 22 · 2019: 21 · 2018: 25 · 2017: 15 · 2016: 5
- FWCI
- 11.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (F31HL129743, U01HL111018)
- National Human Genome Research Institute (U01HG007900)
- National Institute of General Medical Sciences (T32GM007754, T32GM071340)
- National Institute of Allergy and Infectious Diseases (F31AI124563)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD040372)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- glucocorticoid receptor, glucocorticoid response element, transcription factor binding sites, enhancer clusters, gene expression regulation, enhancer interactions, A549 cells, transcriptional synergy
- MeSH terms
- A549 Cells, Binding Sites, Dexamethasone, Glucocorticoids, Humans, Protein Binding, Receptors, Glucocorticoid, Transcription Factors, Transcriptional Activation, Genome, Human, Genes, Reporter, Response Elements, Chromatin Immunoprecipitation
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