lBromodomain inhibitor JQ1 reversibly blocks IFN-γ production
lBromodomain inhibitor JQ1 reversibly blocks IFN-γ production
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DOI：
10.1038/s41598-019-46516-x
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发表时间：
2019-07-16
影响因子：
4.6
通讯作者：
Aune, Thomas M.
中科院分区：
文献类型：
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作者：
Gibbons, Hunter R.;Mi, Deborah J.;Aune, Thomas M.
作为一类，“BET”抑制剂破坏溴结构域和外端基序（extra-terminal motif， BET）蛋白BRD2、BRD3、BRD4和BRDT与乙酰化组蛋白的结合，阻止RNA聚合酶2募集到增强子和启动子，尤其是超级增强子，从而抑制基因转录。因此，BET抑制剂可能是治疗癌症和炎症性疾病的有效疗法。例如，小分子BET抑制剂JQ1选择性地抑制MYC，这是一种由超级增强子调控的重要癌基因。ifn - γ是先天免疫和适应性免疫反应的关键细胞因子，也受到超级增强子的调节。在这里，我们发现JQ1抑制了TH1极化PBMC培养、CD4+记忆T细胞和NK细胞中ifn - γ的表达。JQ1处理不会减少IFNG位点上激活的染色质标记，但会取代该位点上的RNA聚合酶II。此外，在去除JQ1后，极化TH1培养物中ifn - γ的表达恢复。我们的研究结果表明，JQ1可以抑制ifn - γ的表达，但抑制是可逆的。因此，BET抑制剂可能会破坏先天和适应性免疫反应的正常功能。
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-gamma, a critical cytokine for both innate and adaptive immune responses, is also regulated by a super-enhancer. Here, we show that JQ1 represses IFN-gamma 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-gamma expression recovers in polarized TH1 cultures following removal of JQ1. Our results show that JQ1 abrogates IFN-gamma expression, but repression is reversible. Thus, BET inhibitors may disrupt the normal functions of the innate and adaptive immune response.