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Anti-inflammatory functions of the glucocorticoid receptor require DNA binding.
Nucleic Acids Res. 48, 8393-8407 (2020)
The glucocorticoid receptor is an important immunosuppressive drug target and metabolic regulator that acts as a ligand-gated transcription factor. Generally, GR's anti-inflammatory effects are attributed to the silencing of inflammatory genes, while its adverse effects are ascribed to the upregulation of metabolic targets. GR binding directly to DNA is proposed to activate, whereas GR tethering to pro-inflammatory transcription factors is thought to repress transcription. Usingmice with a point mutation in GR's zinc finger, that still tether via protein-protein interactions while being unable to recognize DNA, we demonstrate that DNA binding is essential for both transcriptional activation and repression. Performing ChIP-Seq, RNA-Seq and proteomics under inflammatory conditions, we show that DNA recognition is required for the assembly of a functional co-regulator complex to mediate glucocorticoid responses. Our findings may contribute to the development of safer immunomodulators with fewer side effects.
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Times Cited
Times Cited
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11.502
3.156
17
26
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Nuclear Receptors; Metabolism; Multiple; Alpha; Gr
Language
Publication Year
2020
HGF-reported in Year
2020
ISSN (print) / ISBN
0305-1048
e-ISSN
1362-4962
Journal
Nucleic Acids Research
Quellenangaben
Volume: 48,
Issue: 15,
Pages: 8393-8407
Publisher
Oxford University Press
Publishing Place
Great Clarendon St, Oxford Ox2 6dp, England
Reviewing status
Peer reviewed
POF-Topic(s)
90000 - German Center for Diabetes Research
30201 - Metabolic Health
30201 - Metabolic Health
Research field(s)
Helmholtz Diabetes Center
PSP Element(s)
G-501900-227
G-502296-001
G-502296-001
Grants
ERC
European Research Council
German Research Foundation (Emmy Noether Programme)
European Research Council
German Research Foundation (Emmy Noether Programme)
WOS ID
WOS:000574315100020
Scopus ID
85090491142
PubMed ID
32619221
Erfassungsdatum
2020-07-07