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| Status |
Public on May 06, 2019 |
| Title |
TNF induces Glucocorticoid Resistance by reshaping the GR Nuclear Cofactor Profile: Investigation of TNF mediated effects on the GR-DNA binding |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Glucocorticoid resistance (GCR) is defined as an unresponsiveness to the anti-inflammatory properties of glucocorticoids (GCs) and their receptor, the glucocorticoid receptor (GR). It is a serious problem in the management of inflammatory diseases and occurs frequently. The strong pro-inflammatory cytokine TNF induces an acute form of GCR, not only in mice, but also in several cell lines, e.g. in the hepatoma cell line BWTG3, as evidenced by impaired Dexamethasone (Dex)-induced GR-dependent gene expression. We report that TNF has a significant and broad impact on the transcriptional performance of GR, but no impact on nuclear translocation, dimerization or DNA binding capacity of GR. Proteome-wide proximity-mapping (BioID), however, revealed that the GR interactome is strongly modulated by TNF. One GR cofactor that interacts significantly less with the receptor under GCR conditions is p300. NFκB activation and p300 knockdown both reduce transcriptional output of GR, whereas p300 overexpression and NFκB inhibition revert TNF-induced GCR, which is in support of a cofactor reshuffle model. This hypothesis is supported by FRET studies. This mechanism of GCR opens new avenues for therapeutic interventions in GCR diseases
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| Overall design |
Examination od GR-DNA bining trough ChIP-seq in 3 conditions with 3 biological replicates (2 condictions) or two biological replicates (1 condiction) and one input control
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| Contributor(s) |
Dendoncker K, Timmermans S, Vandewalle J, Eggermont M, Lempiäinen J, Van Hamme E, Dewaele S, Vandevyver S, Ballegeer M, Souffriau J, Van Wyngene L, Van Looveren K, Vanderhaeghen T, Beyaert R, De Bosscher K, Palvimo JJ, Van Montagu M, Libert C |
| Citation(s) |
31182584 |
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| Submission date |
Dec 17, 2018 |
| Last update date |
Jun 05, 2021 |
| Contact name |
Steven Timmermans |
| Organization name |
VIB-UGent
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| Street address |
Technologiepark 71
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| City |
Gent |
| ZIP/Postal code |
9052 |
| Country |
Belgium |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA510377 |
| SRA |
SRP173625 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE123953_RAW.tar |
507.8 Mb |
(http)(custom) |
TAR (of BEDGRAPH, TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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