Bromodomain Inhibitor JQ1 Reversibly Blocks IFN-γ Production

Overview

Journal Sci Rep

Specialty Science

Date 2019 Jul 18

PMID 31311960

Citations 26

Authors

Hunter R Gibbons

Deborah J Mi

Virginia M Farley

Tashawna Esmond

Mary B Kaood

Thomas M Aune

Affiliations

Soon will be listed here.

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.

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References

Tato C, Martins G, High F, DiCioccio C, Reiner S, Hunter C . Cutting Edge: Innate production of IFN-gamma by NK cells is independent of epigenetic modification of the IFN-gamma promoter. J Immunol. 2004; 173(3):1514-7. DOI: 10.4049/jimmunol.173.3.1514. View

Hertweck A, Evans C, Eskandarpour M, Lau J, Oleinika K, Jackson I . T-bet Activates Th1 Genes through Mediator and the Super Elongation Complex. Cell Rep. 2016; 15(12):2756-70. PMC: 4920892. DOI: 10.1016/j.celrep.2016.05.054. View

Jiang Y, Veschambre P, Erdjument-Bromage H, Tempst P, Conaway J, Conaway R . Mammalian mediator of transcriptional regulation and its possible role as an end-point of signal transduction pathways. Proc Natl Acad Sci U S A. 1998; 95(15):8538-43. PMC: 21111. DOI: 10.1073/pnas.95.15.8538. View

Spurlock 3rd C, Tossberg J, Guo Y, Collier S, Crooke 3rd P, Aune T . Expression and functions of long noncoding RNAs during human T helper cell differentiation. Nat Commun. 2015; 6:6932. PMC: 4410435. DOI: 10.1038/ncomms7932. View

Nicodeme E, Jeffrey K, Schaefer U, Beinke S, Dewell S, Chung C . Suppression of inflammation by a synthetic histone mimic. Nature. 2010; 468(7327):1119-23. PMC: 5415086. DOI: 10.1038/nature09589. View

Bandukwala H, Gagnon J, Togher S, Greenbaum J, Lamperti E, Parr N . Selective inhibition of CD4+ T-cell cytokine production and autoimmunity by BET protein and c-Myc inhibitors. Proc Natl Acad Sci U S A. 2012; 109(36):14532-7. PMC: 3437860. DOI: 10.1073/pnas.1212264109. View

Huang B, Yang X, Zhou M, Ozato K, Chen L . Brd4 coactivates transcriptional activation of NF-kappaB via specific binding to acetylated RelA. Mol Cell Biol. 2008; 29(5):1375-87. PMC: 2643823. DOI: 10.1128/MCB.01365-08. View

Delmore J, Issa G, Lemieux M, Rahl P, Shi J, Jacobs H . BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011; 146(6):904-17. PMC: 3187920. DOI: 10.1016/j.cell.2011.08.017. View

Yang Z, Yik J, Chen R, He N, Jang M, Ozato K . Recruitment of P-TEFb for stimulation of transcriptional elongation by the bromodomain protein Brd4. Mol Cell. 2005; 19(4):535-45. DOI: 10.1016/j.molcel.2005.06.029. View

10.

Uhlen M, Fagerberg L, Hallstrom B, Lindskog C, Oksvold P, Mardinoglu A . Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419. DOI: 10.1126/science.1260419. View

11.

Scharton T, Scott P . Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. J Exp Med. 1993; 178(2):567-77. PMC: 2191131. DOI: 10.1084/jem.178.2.567. View

12.

Creyghton M, Cheng A, Welstead G, Kooistra T, Carey B, Steine E . Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci U S A. 2010; 107(50):21931-6. PMC: 3003124. DOI: 10.1073/pnas.1016071107. View

13.

Peeters J, Vervoort S, Mijnheer G, de Roock S, Vastert S, Nieuwenhuis E . Autoimmune disease-associated gene expression is reduced by BET-inhibition. Genom Data. 2016; 7:14-7. PMC: 4778599. DOI: 10.1016/j.gdata.2015.11.004. View

14.

Baud M, Lin-Shiao E, Cardote T, Tallant C, Pschibul A, Chan K . Chemical biology. A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes. Science. 2014; 346(6209):638-641. PMC: 4458378. DOI: 10.1126/science.1249830. View

15.

Dos Santos Paparidis N, Durvale M, Canduri F . The emerging picture of CDK9/P-TEFb: more than 20 years of advances since PITALRE. Mol Biosyst. 2016; 13(2):246-276. DOI: 10.1039/c6mb00387g. View

16.

Biron C, Nguyen K, Pien G, Cousens L, Salazar-Mather T . Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol. 1999; 17:189-220. DOI: 10.1146/annurev.immunol.17.1.189. View

17.

Balasubramani A, Mukasa R, Hatton R, Weaver C . Regulation of the Ifng locus in the context of T-lineage specification and plasticity. Immunol Rev. 2010; 238(1):216-32. PMC: 3096439. DOI: 10.1111/j.1600-065X.2010.00961.x. View

18.

Schoenborn J, Wilson C . Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol. 2007; 96:41-101. DOI: 10.1016/S0065-2776(07)96002-2. View

19.

Stetson D, Mohrs M, Reinhardt R, Baron J, Wang Z, Gapin L . Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function. J Exp Med. 2003; 198(7):1069-76. PMC: 2194220. DOI: 10.1084/jem.20030630. View

20.

Ansel K, Lee D, Rao A . An epigenetic view of helper T cell differentiation. Nat Immunol. 2003; 4(7):616-23. DOI: 10.1038/ni0703-616. View