PXD013772-1

PXD013772 is an original dataset announced via ProteomeXchange.

Title	ChIP-MS of GR and GR-DZn in mouse embryonic fibroblasts
Description	The Glucocorticoid Receptor (GR) is both one of the most widely used clinical drug targets and a very potent metabolic regulator. GR belongs to the nuclear hormone receptor family of ligand-gated transcription factors that govern mammalian physiology. Upon ligand binding, GR enters the nucleus to regulate gene expression both positively and negatively. It is known to bind to consensus DNA sequences termed glucocorticoid response elements (GREs), but the mechanisms determining transcriptional activation versus repression remain an unresolved molecular paradox. Prevailing models suggest that tethering of GR to AP-1 or NF-κB via protein-protein interactions, rather than direct DNA binding, specifies negative regulation. However, here we show that the repression of inflammatory genes as well as all other glucocorticoid responses, require direct DNA binding of GR. Generating GR point mutant mice that retain the ability to tether via protein-protein interactions while unable to recognize DNA sequences, we demonstrate that response element recognition via the Zinc finger is absolutely required for both transcriptional activation and repression. We have used ChIP-Seq and RNA-Seq in inflammatory and metabolic cells and tissues together with proteomics to reveal that DNA binding of GR is necessary for the assembly of a functional SWI/SNF coregulator complex. Generally, the desired anti-inflammatory actions of GR are attributed to the silencing of inflammatory genes, while its adverse effects are believed to result from the transcriptional upregulation of metabolic targets. Our findings not only challenge classical models and dogmas of GR mediated gene regulation, but will provide an important basis for the development of novel immunosuppressants with reduced side effect profiles.
HostingRepository	PRIDE
AnnounceDate	2020-07-07
AnnouncementXML	Submission_2020-07-07_06:35:22.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Michael Wierer
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-05-08 05:52:20	ID requested
⏵ 1	2020-07-07 06:35:23	announced
2	2024-10-22 05:08:38	announced	2024-10-22: Updated project metadata.

Escoter-Torres L, Greulich F, Quagliarini F, Wierer M, Uhlenhaut NH, Anti-inflammatory functions of the glucocorticoid receptor require DNA binding. Nucleic Acids Res, 48(15):8393-8407(2020) [pubmed]

curator keyword: Biological, Biomedical

submitter keyword: chromatin, steroid receptor, hormone, coregulator

Matthias Mann
contact affiliation	Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Munich, Germany
contact email	mmann@biochem.mpg.de
lab head
Michael Wierer
contact affiliation	Department of Proteomics and Signal Transduction, Max-Planck Institute of Biochemistry, Martinsried, Germany
contact email	wierer@biochem.mpg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD013772
     1. Label: PRIDE project
     2. Name: ChIP-MS of GR and GR-DZn in mouse embryonic fibroblasts