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Anti-inflammatory functions of the glucocorticoid receptor require DNA binding.

Nucleic Acids Res. 48, 8393-8407 (2020)
Publ. Version/Full Text Research data DOI
Open Access Gold
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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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Publication type Article: Journal article
Document type Scientific Article
Keywords Nuclear Receptors; Metabolism; Multiple; Alpha; Gr
ISSN (print) / ISBN 0305-1048
e-ISSN 1362-4962
Quellenangaben Volume: 48, Issue: 15, Pages: 8393-8407 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Great Clarendon St, Oxford Ox2 6dp, England
Reviewing status Peer reviewed
Grants ERC
European Research Council
German Research Foundation (Emmy Noether Programme)