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Single-nucleotide methylation specifically represses type I interferon in antiviral innate immunity.
单核苷酸甲基化特异性抑制抗病毒天然免疫中的I型干扰素。
- 影响因子:9.83
- DOI:10.1084/jem.20201798
- 作者列表:"Gao ZJ","Li WP","Mao XT","Huang T","Wang HL","Li YN","Liu BQ","Zhong JY","Renjie C","Jin J","Li YY
- 发表时间:2021-03-01
Abstract
:Frequent outbreaks of viruses have caused a serious threat to public health. Previous evidence has revealed that DNA methylation is correlated with viral infections, but its role in innate immunity remains poorly investigated. Additionally, DNA methylation inhibitors promote IFN-I by upregulating endogenous retrovirus; however, studies of intrinsically demethylated tumors do not support this conclusion. This study found that Uhrf1 deficiency in myeloid cells significantly upregulated Ifnb expression, increasing resistance to viral infection. We performed whole-genome bisulfite sequencing and found that a single-nucleotide methylation site in the Ifnb promoter region disrupted IRF3 recruitment. We used site-specific mutant knock-in mice and a region-specific demethylation tool to confirm that this methylated site plays a critical role in regulating Ifnb expression and antiviral responses. These findings provide essential insight into DNA methylation in the regulation of the innate antiviral immune response.
摘要
: 病毒的频繁爆发对公众健康造成了严重威胁。先前的证据已经揭示DNA甲基化与病毒感染相关,但其在先天免疫中的作用仍然缺乏研究。此外,DNA甲基化抑制剂通过上调内源性逆转录病毒促进IFN-I; 然而,固有去甲基化肿瘤的研究不支持这一结论。该研究发现,髓样细胞中的Uhrf1缺陷显著上调Ifnb表达,增加对病毒感染的抗性。我们进行了全基因组亚硫酸氢盐测序,发现Ifnb启动子区的一个单核苷酸甲基化位点破坏了IRF3募集。我们使用位点特异性突变敲入小鼠和区域特异性去甲基化工具来证实这个甲基化位点在调节Ifnb表达和抗病毒反应中起关键作用。这些发现提供了DNA甲基化在先天性抗病毒免疫应答调节中的重要见解。
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