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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.

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 20??M), 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.

SUBMITTER: Garcia-Faroldi G

PROVIDER: S-EPMC5418135 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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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 G Rönnberg Elin E Grujic Mirjana M Pejler Gunnar G

Immunity, inflammation and disease 20170313 2

<h4>Introduction</h4>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.<h4>Methods</h4>We assessed the effects ...[more]

PMID: 28474499

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Project description:Epigenetic mechanisms involve the placing (writing) or removal (erasing) of histone modifications that allow heterochromatin to transition to the open, activated euchromatin state necessary for transcription. A third, less studied epigenetic pathway involves the reading of these specific histone marks once placed. The BETs (bromodomain and extraterminal-containing protein family), which includes BRD2, BRD3, and BRD4 and the testis-restricted BRDT, are epigenetic reader proteins that bind to specific acetylated lysine residues on histone tails where they facilitate the assembly of transcription complexes including transcription factors and transcriptional machinery like RNA Polymerase II. As reviewed here, considerable recent data establishes BETs as novel determinants of induced transcriptional programs in vascular cells, like endothelial cells and vascular smooth muscle cells, cardiac myocytes and inflammatory cells, like monocyte/macrophages, cellular settings where these epigenetic reader proteins couple proximal stimuli to chromatin, acting at super-enhancer regulatory regions to direct gene expression. BET inhibition, including the use of specific chemical BET inhibitors like JQ-1, has many reported effects in vivo in the cardiovascular setting, like decreasing atherosclerosis, angiogenesis, intimal hyperplasia, pulmonary arterial hypertension, and cardiac hypertrophy. At the same time, data in endothelial cells, adipocytes, and elsewhere suggest BETs also help regulate gene expression under basal conditions. Studies in the cardiovascular setting have highlighted BET action as a means of controlling gene expression in differentiation, cell identity, and cell state transitions, whether physiological or pathological, adaptive, or maladaptive. While distinct BET inhibitors are being pursued as therapies in oncology, a large prospective clinical cardiovascular outcome study investigating the BET inhibitor RVX-208 (now called apabetalone) has already been completed. Independent of this specific agent and this one trial or the numerous unanswered questions that remain, BETs have emerged as novel epigenetic players involved in the execution of coordinated transcriptional programs in cardiovascular health and disease.

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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.

Publications

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

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