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Inhibition of the BET family of epigenetic reader proteins: A novel principle for modulating gene expression in IgE-activated mast cells

Garcia-Faroldi, Gianni and Ronnberg, Elin and Grujic, Mirjana and Pejler, Gunnar (2017). Inhibition of the BET family of epigenetic reader proteins: A novel principle for modulating gene expression in IgE-activated mast cells. Immunity, Inflammation and Disease. 5 , 141-150
[Research article]

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Abstract

Introduction: The BET family of bromodomain-containing proteins constitute epigenetic readers that bind to acetylated lysine residues of core histones, thereby translating epigenetic histone marks to effects on gene expression. BET inhibitors are currently emerging as promising therapeutic agents for treatment of various pathological conditions. Here, we explored the potential of using BET inhibition to modulate IgE-mediated responses in mast cells.Methods: We assessed the effects of BET inhibitors PFI-1, I-BET151, and I-BET762 on responses downstream of mast cell activation through IgE receptor cross-linking.Results: BET inhibitors were neither toxic for mast cells (at doses up to 20M), nor did they prevent IgE-mediated mast cell degranulation. However, we found that BET inhibition, in particular by I-BET151, suppressed IL-6 gene expression and IL-6 protein release in response to IgE-mediated mast cell activation. This was observed in both bone marrow-derived mast cells (BMMCs) and in mature peritoneal-cell derived mast cells. Further analysis showed that BET inhibition also suppressed the expression of a number of additional genes of those that were upregulated by IgE receptor cross-linking, including IL-3, IL-7R, CCR1, and ADAMTS9. However, BET inhibition was selective, i.e., several genes that were upregulated by IgE receptor cross-linking were not affected by BET inhibitors.Conclusions: These findings suggest that BET inhibition can interfere with the upregulated expression of selected genes in mast cells activated by IgE receptor cross-linking. Further, our findings introduce the concept of utilizing epigenetic mechanisms for modulating mast cell function in the context of IgE-driven disease.

Authors/Creators:Garcia-Faroldi, Gianni and Ronnberg, Elin and Grujic, Mirjana and Pejler, Gunnar
Title:Inhibition of the BET family of epigenetic reader proteins: A novel principle for modulating gene expression in IgE-activated mast cells
Series Name/Journal:Immunity, Inflammation and Disease
Year of publishing :2017
Volume:5
Page range:141-150
Number of Pages:10
Publisher:WILEY
ISSN:2050-4527
Language:English
Publication Type:Research article
Article category:Scientific peer reviewed
Version:Published version
Copyright:Creative Commons: Attribution 4.0
Full Text Status:Public
Subjects:(A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 301 Basic Medicine > Immunology in the medical area
Keywords:BET proteins, epigenetics, IgE, IL-6, mast cells
URN:NBN:urn:nbn:se:slu:epsilon-p-112495
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-p-112495
Additional ID:
Type of IDID
DOI10.1002/iid3.150
Web of Science (WoS)000400784000005
ID Code:24665
Faculty:VH - Faculty of Veterinary Medicine and Animal Science
Department:(VH) > Dept. of Anatomy, Physiology and Biochemistry
Deposited By: SLUpub Connector
Deposited On:22 Jun 2021 12:43
Metadata Last Modified:22 Jun 2021 12:51

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