Cited by 182Genomics and Chromatin DynamicsEstrogen and related hormone effectsChromatin Remodeling and Cancer

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

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Vockley, Christopher M., D’Ippolito, Anthony M., McDowell, Ian C., Majoros, William H., Safi, Alexias, Song, Lingyun, Crawford, Gregory E., Reddy, Timothy E.·2016·Cell

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.

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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.”

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  1. Love MI Huber W Anders S Moderated estimation of fold change and dispersion for RNA-Seq data with DESeq2 2014a PMC4302049 25516281

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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.
Venue
Cell
Publisher
Elsevier BV
Published
2016-08
Volume
166
Issue
5
Pages
1269-1281.e19
ISSN
0092-8674 (ISSN-L)
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
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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