Bromodomain Protein Inhibitors Reorganize the Chromatin of Synovial Fibroblasts

Monika Krošel, Larissa Moser, Miranda Houtman, Jasna Friščić, Matija Tomšič, Oliver Distler, Markus H. Hoffmann, Caroline Ospelt, Kerstin Klein*

*Corresponding author for this work

Abstract

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.

Original languageEnglish
Article number1149
JournalCells
Volume12
Issue number8
ISSN1066-5099
DOIs
Publication statusPublished - 13.04.2023

Research Areas and Centers

  • Academic Focus: Center for Infection and Inflammation Research (ZIEL)
  • Centers: Center for Research on Inflammation of the Skin (CRIS)

DFG Research Classification Scheme

  • 2.21-05 Immunology

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  • CRC 1526, PANTAU: Pathomechanisms of Antibody-mediated Autoimmunity

    Sadik, C. (Speaker, Coordinator), Zillikens, D. (Speaker, Coordinator), Scheffold, A. (Principal Investigator (PI)), Schmidt, E. (Principal Investigator (PI)), Heine, G. (Principal Investigator (PI)), Manz, R. (Principal Investigator (PI)), Köhl, J. (Principal Investigator (PI)), Ludwig, R. (Principal Investigator (PI)), Peipp, M. (Principal Investigator (PI)), Hammers, M. C. (Principal Investigator (PI)), Verschoor, A. (Principal Investigator (PI)), Karsten, C. (Principal Investigator (PI)), Nimmerjahn, F. (Principal Investigator (PI)), Hutloff, A. (Principal Investigator (PI)), Ibrahim, S. (Principal Investigator (PI)), Wettschureck, N. (Principal Investigator (PI)), Bieber, K. (Principal Investigator (PI)), Schilf, P. (Principal Investigator (PI)), Vaeth, M. (Principal Investigator (PI)), Hirose, M. (Principal Investigator (PI)), Vaeth, M. (Principal Investigator (PI)), Baines, J. F. (Principal Investigator (PI)), Bacher, P. (Principal Investigator (PI)), Hoffmann, M. (Principal Investigator (PI)), Busch, H. S. (Principal Investigator (PI)), Höppner, M. (Principal Investigator (PI)), Becker, M. (Principal Investigator (PI)), Holtsche, M. M. (Principal Investigator (PI)), Fähnrich, A. (Principal Investigator (PI)), Szymczak, S. (Principal Investigator (PI)), Murthy, S. (Principal Investigator (PI)) & Lux, A. (Principal Investigator (PI))

    01.01.22 → …

    Project: DFG ProjectsDFG Joint Research: Collaborative Research Center/ Transregios

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