4.7 Article

Single-nucleotide methylation specifically represses type I interferon in antiviral innate immunity

Journal

JOURNAL OF EXPERIMENTAL MEDICINE
Volume 218, Issue 3, Pages -

Publisher

ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20201798

Keywords

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Funding

  1. National Key Research and Development Program of China [2018YFD0500100, 2018YFA0800503]
  2. Excellent Young Scientist Fund of National Natural Science Foundation of China [31822017]
  3. Natural Science Foundation of Zhejiang Province [LR19C080001]
  4. National Natural Science Foundation of China [81771675, 81970484]
  5. Key Research and Development Program of Zhejiang Province [2020C03075]

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This study reveals that deficiency of Uhrf1 in myeloid cells significantly upregulates Ifnb expression, enhancing resistance to viral infection. Whole-genome bisulfite sequencing identified a single nucleotide methylation site in the Ifnb promoter region that disrupts IRF3 recruitment. Further experiments confirmed the critical role of this methylated site in regulating Ifnb expression and antiviral responses.
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.

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