Recruitment of histone deacetylase 3 to the interferon-A gene promoters attenuates interferon expression.
Recruitment of histone deacetylase 3 to the interferon-A gene promoters attenuates interferon expression.
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DOI：
10.1371/journal.pone.0038336
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Civas A
中科院分区：
文献类型：
--
作者：
Génin P;Lin R;Hiscott J;Civas A
I型干扰素（IFN）基因的诱导构成了在病毒感染期间导致先天免疫应答的必要步骤。仙台病毒（SeV）感染B淋巴Namalwa细胞瞬时诱导多个IFN-A基因的转录表达。虽然IFN-A基因的转录激活已被广泛研究，但其表达减弱的机制仍有待确定。在这项研究中，我们证明，病毒感染Namalwa细胞诱导瞬时招募HDAC 3（组蛋白脱乙酰酶3）IFN-A启动子。通过Chip-QPCR分析染色质-蛋白质缔合表明干扰素调节因子（IRF）3和IRF 7以及TBP的募集与增强的组蛋白H3 K9和H3 K14乙酰化相关，而HDAC 3的募集与组蛋白H3 K9/K14乙酰化的抑制相关，从IFN-A启动子中去除IRF 7和TATA结合蛋白（TBP）并抑制病毒诱导的IFN-A基因转录。此外，HDAC 3过表达减少，并且通过siRNA去除HDAC 3增强IFN-A基因表达。此外，IRF 7的活化增强组蛋白H3 K9/K14乙酰化和IFN-A基因表达，而IRF 7和IRF 3两者的活化导致HDAC 3募集到IFN-A基因启动子，导致组蛋白H3 K9乙酰化受损和IFN-A基因转录减弱。总之，这些数据表明，HDAC 3逆转组蛋白H3 K9/K14乙酰化是病毒感染期间IFN-A基因转录减弱所必需的。
Induction of Type I Interferon (IFN) genes constitutes an essential step leading to innate immune responses during virus infection. Sendai virus (SeV) infection of B lymphoid Namalwa cells transiently induces the transcriptional expression of multiple IFN-A genes. Although transcriptional activation of IFN-A genes has been extensively studied, the mechanism responsible for the attenuation of their expression remains to be determined. In this study, we demonstrate that virus infection of Namalwa cells induces transient recruitment of HDAC3 (histone deacetylase 3) to IFN-A promoters. Analysis of chromatin-protein association by Chip-QPCR demonstrated that recruitment of interferon regulatory factor (IRF)3 and IRF7, as well as TBP correlated with enhanced histone H3K9 and H3K14 acetylation, whereas recruitment of HDAC3 correlated with inhibition of histone H3K9/K14 acetylation, removal of IRF7 and TATA-binding protein (TBP) from IFN-A promoters and inhibition of virus-induced IFN-A gene transcription. Additionally, HDAC3 overexpression reduced, and HDAC3 depletion by siRNA enhanced IFN-A gene expression. Furthermore, activation of IRF7 enhanced histone H3K9/K14 acetylation and IFN-A gene expression, whereas activation of both IRF7 and IRF3 led to recruitment of HDAC3 to the IFN-A gene promoters, resulting in impaired histone H3K9 acetylation and attenuation of IFN-A gene transcription. Altogether these data indicate that reversal of histone H3K9/K14 acetylation by HDAC3 is required for attenuation of IFN-A gene transcription during viral infection.
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