Krošel, Monika; Moser, Larissa; Houtman, Miranda; Friščić, Jasna; Tomšič, Matija; Distler, Oliver; Hoffmann, Markus H; Ospelt, Caroline; Klein, Kerstin (2023). Bromodomain Protein Inhibitors Reorganize the Chromatin of Synovial Fibroblasts. Cells, 12(8) MDPI 10.3390/cells12081149
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Bromodomain- and extra-terminal domain (BET) proteins are epigenetic reader proteins that regulate transcription of their target genes by binding to acetylated histone side chains. Small molecule inhibitors, such as I-BET151, have anti-inflammatory properties in fibroblast-like synoviocytes (FLS) and in animal models of arthritis. Here, we investigated whether BET inhibition can also affect the levels of histone modifications, a novel mechanism underlying BET protein inhibition. On the one hand, FLSs were treated with I-BET151 (1 µM) for 24 h in absence and presence of TNF. On the other hand, FLSs were washed with PBS after 48 h of I-BET151 treatment, and the effects were measured 5 days after I-BET151 treatment or after an additional 24 h stimulation with TNF (5 d + 24 h). Mass spectrometry analysis indicated that I-BET151 induced profound changes in histone modifications, with a global reduction in acetylation on different histone side chains 5 days after treatment. We confirmed changes on acetylated histone side chains in independent samples by Western blotting. I-BET151 treatment reduced mean TNF-induced levels of total acetylated histone 3 (acH3), H3K18ac, and H3K27ac. In line with these changes, the TNF-induced expression of BET protein target genes was suppressed 5 d after I-BET151 treatment. Our data indicate that BET inhibitors not only prevent the reading of acetylated histones but directly influence overall chromatin organization, in particular after stimulation with TNF.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Rheumatologie 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Rheumatologie 04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Rheumatology and Immunology |
UniBE Contributor: |
Klein, Kerstin |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
2073-4409 |
Publisher: |
MDPI |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
17 May 2023 13:59 |
Last Modified: |
17 May 2023 14:08 |
Publisher DOI: |
10.3390/cells12081149 |
PubMed ID: |
37190058 |
Uncontrolled Keywords: |
BET bromodomain protein I-BET chromatin organization histone acetylation |
BORIS DOI: |
10.48350/182631 |
URI: |
https://boris.unibe.ch/id/eprint/182631 |
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