Abstract
As a class, ‘BET’ inhibitors disrupt binding of bromodomain and extra-terminal motif (BET) proteins, BRD2, BRD3, BRD4 and BRDT, to acetylated histones preventing recruitment of RNA polymerase 2 to enhancers and promoters, especially super-enhancers, to inhibit gene transcription. As such, BET inhibitors may be useful therapeutics for treatment of cancer and inflammatory disease. For example, the small molecule BET inhibitor, JQ1, selectively represses MYC, an important oncogene regulated by a super-enhancer. IFN-γ, a critical cytokine for both innate and adaptive immune responses, is also regulated by a super-enhancer. Here, we show that JQ1 represses IFN-γ expression in TH1 polarized PBMC cultures, CD4+ memory T cells, and NK cells. JQ1 treatment does not reduce activating chromatin marks at the IFNG locus, but displaces RNA polymerase II from the locus. Further, IFN-γ expression recovers in polarized TH1 cultures following removal of JQ1. Our results show that JQ1 abrogates IFN-γ expression, but repression is reversible. Thus, BET inhibitors may disrupt the normal functions of the innate and adaptive immune response.
Highlights
Bromodomain and extraterminal domain (BET) proteins are a family of transcriptional mediators, which assist in the recruitment of RNA Polymerase II (RNA pol II) to enhancers and promoters[1,2]
These results indicate that JQ1 treatment significantly inhibited IFNG mRNA expression by TH1 polarized PBMC cultures
Total RNA isolated from natural killer (NK) cells did not significantly change according to JQ1 treatment, indicating cell viability and total cellular RNA yield were not affected by the JQ1 treatments (Fig. 3D). These results indicate that IFNG expression was significantly reduced in NK cells following JQ1 treatment, similar to TH1 polarized PBMC cultures and memory CD4+ T cells
Summary
Bromodomain and extraterminal domain (BET) proteins are a family of transcriptional mediators, which assist in the recruitment of RNA Polymerase II (RNA pol II) to enhancers and promoters[1,2]. This family of proteins consists of BRD2, BRD3, BRD4, and BRDT. JQ1 represses MYC expression by interrupting the Mediator-BRD4 complexes located in its super-enhancer region[11,14]. Despite its potential as a cancer treatment, JQ1 inhibitors repress the expression of multiple genes, oncogenes[23]. Inhibition of IFN-γ expression by JQ1 is not irreversible as ability of TH1 polarized PBMC cultures to produce IFN-γ is recovered after removal of JQ1
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