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Dynamic Exchange at Regulatory Elements during Chromatin Remodeling Underlies Assisted Loading Mechanism
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The glucocorticoid receptor (GR), like other eukaryotic transcription factors, regulates gene expression by interacting with chromatinized DNA response elements. Photobleaching experiments in living cells indicate that receptors transiently interact with DNA on the time scale of seconds and predict that the response elements may be sparsely occupied on average. Here, we show that the binding of one receptor at the glucocorticoid response element (GRE) does not reduce the steady-state binding of another receptor variant to the same GRE. Mathematical simulations reproduce this noncompetitive state using short GR/GRE residency times and relatively long times between DNA binding events. At many genomic sites where GR binding causes increased chromatin accessibility, concurrent steady-state binding levels for the variant receptor are actually increased, a phenomenon termed assisted loading. Temporally sparse transcription factor-DNA interactions induce local chromatin reorganization, resulting in transient access for binding of secondary regulatory factors.
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“Once in the nucleus, liganded GRs do not bind to DNA in a stable manner. They rather constantly shuttle between the nucleoplasm and GC-responsive elements (GRE) located in the promoter or enhancer regions of GC-responsive genes (80, 81).”
From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [81]
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Metadata
- Authors
- Voss, T. C., Schiltz, R. L., Sung, M.-H., Yen, P. M., Stamatoyannopoulos, J. A., Biddie, S. C., Johnson, T. A., Miranda, T. B., John, S., & Hager, G. L.
- Affiliations
- National Institutes of Health (US)
- National University of Singapore (SG)
- University of Washington (US)
- Corresponding author
- Hager, Gordon L.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2011-08
- Volume
- 146
- Issue
- 4
- Pages
- 544-554
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3210475
- OpenAlex
- W1963958393
- Cited by
- 307
- References
- 42
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 11 · 2023: 11 · 2022: 16 · 2021: 20 · 2020: 17 · 2019: 23 · 2018: 33 · 2017: 23 · 2016: 29 · 2015: 23 · 2014: 25 · 2013: 26 · 2012: 29
- FWCI
- 11.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (ZIABC005450)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Diffusion and Search Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- glucocorticoid receptor, glucocorticoid response element, transcription factor-DNA binding, chromatin accessibility, chromatin remodeling, receptor isoforms, photobleaching, transcriptional regulation
- MeSH terms
- Adenosine Triphosphate, Animals, Mammary Tumor Virus, Mouse, Models, Biological, Monte Carlo Method, Nucleosomes, Receptors, Estrogen, Receptors, Glucocorticoid, Regulatory Sequences, Nucleic Acid, Transcription Factors, Response Elements, Chromatin Assembly and Disassembly, Cell Line, Tumor, Mice
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