Glucocorticoid receptor recruits to enhancers and drives activation by motif-directed binding

  1. Timothy E. Reddy1,2,3,4,6,10
  1. 1Graduate Program in Computational Biology and Bioinformatics, Duke University, Durham, North Carolina 27708, USA;
  2. 2Center for Genomic and Computational Biology, Duke University, Durham, North Carolina 27708, USA;
  3. 3Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina 27708, USA;
  4. 4University Program in Genetics and Genomics, Duke University, Durham, North Carolina 27708, USA;
  5. 5Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27708, USA;
  6. 6Department of Biomedical Engineering, Duke University, Durham, North Carolina 27708, USA;
  7. 7Department of Orthopaedic Surgery, Duke University Medical Center, Durham, North Carolina 27708, USA;
  8. 8Department of Computer Science, Duke University, Durham, North Carolina 27708, USA;
  9. 9Department of Biology, Duke University, Durham, North Carolina 27708, USA;
  10. 10Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina 27708, USA;
  11. 11Department of Computer Science, Princeton University, Princeton, New Jersey 08540, USA;
  12. 12Center for Statistics and Machine Learning, Princeton University, Princeton, New Jersey 08540, USA
  • Corresponding authors: tim.reddy{at}duke.edu, amink{at}cs.duke.edu, greg.crawford{at}duke.edu, bee{at}princeton.edu
  • Abstract

    Glucocorticoids are potent steroid hormones that regulate immunity and metabolism by activating the transcription factor (TF) activity of glucocorticoid receptor (GR). Previous models have proposed that DNA binding motifs and sites of chromatin accessibility predetermine GR binding and activity. However, there are vast excesses of both features relative to the number of GR binding sites. Thus, these features alone are unlikely to account for the specificity of GR binding and activity. To identify genomic and epigenetic contributions to GR binding specificity and the downstream changes resultant from GR binding, we performed hundreds of genome-wide measurements of TF binding, epigenetic state, and gene expression across a 12-h time course of glucocorticoid exposure. We found that glucocorticoid treatment induces GR to bind to nearly all pre-established enhancers within minutes. However, GR binds to only a small fraction of the set of accessible sites that lack enhancer marks. Once GR is bound to enhancers, a combination of enhancer motif composition and interactions between enhancers then determines the strength and persistence of GR binding, which consequently correlates with dramatic shifts in enhancer activation. Over the course of several hours, highly coordinated changes in TF binding and histone modification occupancy occur specifically within enhancers, and these changes correlate with changes in the expression of nearby genes. Following GR binding, changes in the binding of other TFs precede changes in chromatin accessibility, suggesting that other TFs are also sensitive to genomic features beyond that of accessibility.

    Footnotes

    • Present addresses: 14The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; 15Sequencing and Genomic Technologies Shared Resource, Durham, NC 27701, USA; 16Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA

    • [Supplemental material is available for this article.]

    • Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.233346.117.

    • Freely available online through the Genome Research Open Access option.

    • Received December 4, 2017.
    • Accepted July 5, 2018.

    This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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