title: Dynamics of chromatin accessibility and long-range interactions in response to glucocorticoid pulsing.
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.
authors: Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA;
authors: Diana A
authors: DA
authors: Stavreva
authors: Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA;
authors: Antoine
authors: A
authors: Coulon
authors: Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA;
authors: Songjoon
authors: S
authors: Baek
authors: Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA;
authors: Myong-Hee
authors: MH
authors: Sung
authors: Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA;
authors: Sam
authors: S
authors: John
authors: Department of Molecular Cytology and Cytometry, Institute of Biophysics, Academy of Sciences of the Czech Republic, 612 65 Brno, Czech Republic;
authors: Lenka
authors: L
authors: Stixova
authors: Department of Biosciences, University of Oslo, 0316 Oslo, Norway;
authors: Martina
authors: M
authors: Tesikova
authors: The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel;
authors: Ofir
authors: O
authors: Hakim
authors: Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA;
authors: Tina
authors: T
authors: Miranda
authors: Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA;
authors: Mary
authors: M
authors: Hawkins
authors: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors: John A
authors: JA
authors: Stamatoyannopoulos
authors: Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA;
authors: Carson C
authors: CC
authors: Chow
authors: Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA;
authors: Gordon L
authors: GL
authors: Hager
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D003850:Deoxyribonuclease I / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000071229:Perilipin-4; D011485:Protein Binding; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D017422:Sequence Analysis, DNA
chemical_list: D002352:Carrier Proteins; D002843:Chromatin; D005938:Glucocorticoids; D008565:Membrane Proteins; D000071229:Perilipin-4; C487119:Plin4 protein, mouse; D011965:Receptors, Glucocorticoid; D003850:Deoxyribonuclease I