Dynamics of chromatin accessibility and long-range interactions in response to glucocorticoid pulsing
- Diana A. Stavreva1,8,
- Antoine Coulon2,8,
- Songjoon Baek1,
- Myong-Hee Sung1,
- Sam John3,
- Lenka Stixova4,
- Martina Tesikova5,
- Ofir Hakim6,
- Tina Miranda1,
- Mary Hawkins1,
- John A. Stamatoyannopoulos7,
- Carson C. Chow2 and
- Gordon L. Hager1
- 1Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA;
- 2Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA;
- 3Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA;
- 4Department of Molecular Cytology and Cytometry, Institute of Biophysics, Academy of Sciences of the Czech Republic, 612 65 Brno, Czech Republic;
- 5Department of Biosciences, University of Oslo, 0316 Oslo, Norway;
- 6The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel;
- 7Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA
- Corresponding authors: hagerg{at}exchange.nih.gov, stavrevd{at}mail.nih.gov
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↵8 These authors contributed equally to this work.
Abstract
Although physiological steroid levels are often pulsatile (ultradian), the genomic effects of this pulsatility are poorly understood. By utilizing glucocorticoid receptor (GR) signaling as a model system, we uncovered striking spatiotemporal relationships between receptor loading, lifetimes of the DNase I hypersensitivity sites (DHSs), long-range interactions, and gene regulation. We found that hormone-induced DHSs were enriched within ±50 kb of GR-responsive genes and displayed a broad spectrum of lifetimes upon hormone withdrawal. These lifetimes dictate the strength of the DHS interactions with gene targets and contribute to gene regulation from a distance. Our results demonstrate that pulsatile and constant hormone stimulations induce unique, treatment-specific patterns of gene and regulatory element activation. These modes of activation have implications for corticosteroid function in vivo and for steroid therapies in various clinical settings.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.184168.114.
- Received September 9, 2014.
- Accepted February 5, 2015.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
