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.

Department of Biosciences University of Oslo 0316 Oslo Norway;

Department of Genome Sciences University of Washington Seattle Washington 98195 USA

Department of Molecular Cytology and Cytometry Institute of Biophysics Academy of Sciences of the Czech Republic 612 65 Brno Czech Republic;

Laboratory of Biological Modeling National Institute of Diabetes and Digestive and Kidney Diseases NIH Bethesda Maryland 20892 USA;

Laboratory of Genome Integrity National Cancer Institute NIH Bethesda Maryland 20892 USA;

Laboratory of Receptor Biology and Gene Expression National Cancer Institute NIH Bethesda Maryland 20892 USA;

The Mina and Everard Goodman Faculty of Life Sciences Bar Ilan University Ramat Gan 5290002 Israel;

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