Genomic determination of the glucocorticoid response reveals unexpected mechanisms of gene regulation
Open accessAbstract
The glucocorticoid steroid hormone cortisol is released by the adrenal glands in response to stress and serves as a messenger in circadian rhythms. Transcriptional responses to this hormonal signal are mediated by the glucocorticoid receptor (GR). We determined GR binding throughout the human genome by using chromatin immunoprecipitation followed by next-generation DNA sequencing, and measured related changes in gene expression with mRNA sequencing in response to the glucocorticoid dexamethasone (DEX). We identified 4392 genomic positions occupied by the GR and 234 genes with significant changes in expression in response to DEX. This genomic census revealed striking differences between gene activation and repression by the GR. While genes activated with DEX treatment have GR bound within a median distance of 11 kb from the transcriptional start site (TSS), the nearest GR binding for genes repressed with DEX treatment is a median of 146 kb from the TSS, suggesting that DEX-mediated repression occurs independently of promoter-proximal GR binding. In addition to the dramatic differences in proximity of GR binding, we found differences in the kinetics of gene expression response for induced and repressed genes, with repression occurring substantially after induction. We also found that the GR can respond to different levels of corticosteroids in a gene-specific manner. For example, low doses of DEX selectively induced PER1 , a transcription factor involved in regulating circadian rhythms. Overall, the genome-wide determination and analysis of GR:DNA binding and transcriptional response to hormone reveals new insights into the complexities of gene regulatory activities managed by GR.
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GCs modulate the cellular transcriptional landscape through the GC receptor, affecting up to 20% of all genes.
“Through action on the cytosolic GC receptor (GR), GCs profoundly modulate the cellular transcriptional landscape,24 affecting up to 20% of all genes25”
From Cystatin C is glucocorticoid responsive, directs recruitment of Trem2+ macrophages, and predicts failure of cancer immunotherapy (2023) · cites this paper as [24]
The ‘Identification of GC-responsive genes by RNA-seq’ section reports that dexamethasone changed gene expression, supporting the claim that glucocorticoids affect transcription. But it identifies 209 differentially expressed genes among 29,673 assessed—not a figure approaching 20% of all genes. The cited paper does not support the attributed 20% figure. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe ChIP-seq protocols used were similar to those previously described by the authors' lab and consistent with ENCODE Consortium recommendations.
“Protocols for ChIP-seq are similar to those for frozen tissue previously described by our lab115,116 and consistent with techniques recommended by the ENCODE Consortium (www.encodeproject.org/documents).”
From Single nucleus multiomics identifies ZEB1 and MAFB as candidate regulators of Alzheimer’s disease-specific cis-regulatory elements (2023) · cites this paper as [116]
Ligand-activated GR induces or represses thousands of genes by directly binding DNA response elements, by physically associating with other transcription factors, or by both mechanisms.
“Ligand-activated GR induces or represses the transcription of thousands of genes through direct binding to DNA response elements, physically associating with other transcription factors, or both.”
From Corticosteroids (2016) · cites this paper as [22]
Many GR-binding sites are far from promoter-proximal regions of target genes, and the activation and repressive functions of GR differ unexpectedly.
“Comprehensive GR binding analyses revealed that many GR-binding sites identified are located far from the promoter proximal region of target genes and showed an unexpected difference between the activation and repressive functions of the GR [22].”
From Corticosteroids (2016) · cites this paper as [22]
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Self-citationCETCh-seq: CRISPR epitope tagging ChIP-seq of DNA-binding proteinsPreprint
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Self-citationNucleosome-Driven Transcription Factor Binding and Gene Regulation
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Cancer cell proliferation is inhibited by specific modulation frequencies
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Self-citationAnti-inflammatory Chromatinscape Suggests Alternative Mechanisms of Glucocorticoid Receptor Action
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Exploring the Molecular Mechanisms of Glucocorticoid Receptor Action from Sensitivity to Resistance
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Glucocorticoid receptor dimerization induces MKP1 to protect against TNF-induced inflammation
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Cryptic glucocorticoid receptor-binding sites pervade genomic NF-κB response elements
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Role of Dual-Specificity Phosphatase 1 in Glucocorticoid-Driven Anti-inflammatory Responses
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Effects of the Circadian Rhythm Gene Period 1 (Per1) on Psychosocial Stress-Induced Alcohol Drinking
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Selective Glucocorticoid Receptor modulators
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Antitumor activity of a pyrrole-imidazole polyamide
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High-Resolution Genome-wide Mapping of AHR and ARNT Binding Sites by ChIP-Seq
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Regulation of triglyceride metabolism by glucocorticoid receptor
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Glucocorticoid receptor recruits to enhancers and drives activation by motif-directed bindingPreprint
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Self-citationGlucocorticoid-mediated Period2 induction delays the phase of circadian rhythm
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Transversions have larger regulatory effects than transitions
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Self-citationA map of the PPARα transcription regulatory network for primary human hepatocytes
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Glucocorticoid resistance as a major drive in sepsis pathology
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- Authors
- Reddy, T. E., Pauli, F., Sprouse, R. O., Neff, N. F., Newberry, K. M., Garabedian, M. J., & Myers, R. M.
- Affiliations
- HudsonAlpha Institute for Biotechnology (US)
- Stanford Medicine (US)
- New York University (US)
- ORCID
- Venue
- Genome Research
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2009-10-02
- Volume
- 19
- Issue
- 12
- Pages
- 2163-2171
- ISSN
- 1088-9051 (ISSN-L)
- PMC
- PMC2792167
- OpenAlex
- W2113112889
- Cited by
- 543
- References
- 44
- Citations by year
- 2026: 16 · 2025: 15 · 2024: 32 · 2023: 35 · 2022: 25 · 2021: 28 · 2020: 29 · 2019: 35 · 2018: 34 · 2017: 47 · 2016: 49 · 2015: 41 · 2014: 32 · 2013: 35 · 2012: 38
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genome Research (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Philip Morris International
- National Institutes of Health
- National Human Genome Research Institute (U54HG004576)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- glucocorticoid receptor, dexamethasone, cortisol, transcriptional repression, transcriptional activation, Per1, circadian rhythm, hormone dose-response, gene expression regulation
- MeSH terms
- Binding Sites, Dexamethasone, Gene Expression Regulation, Humans, Lung, Proteins, Receptors, Glucocorticoid, RNA, Messenger, Genome, Sequence Analysis, DNA, Chromatin Immunoprecipitation
About these checks
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