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

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.

Cross-species analysis of viral nucleic acid interacting proteins identifies TAOKs as innate immune regulators

“…3b ). Moreover, in this screening system depletion of the DNA interactor UHRF1 , a chromatin modifier linked to negative regulation of IFN-β expression 55 , surprisingly promoted the growth of HSV-1, which could be in line with specific antiviral activity against DNA viruses and may call for further functional studies on this protein. Among proteins with a proviral activity, we identified the poly(I:C) and poly(A:U) associating proteins KHDRBS1, APEX1, and MKRN2 (associate with dsRNA and are proviral for SFV).…”

Epigenetic and transcriptional control of interferon-β

“…Although the classical understanding of the function of UHRF1 is to propagate hemimethylated DNA through DNMT1 recruitment, the findings of Gao et al (2021) invoke a novel function of UHRF1 in repressing IFNβ in the absence of activating signals.…”

“…Beyond histone posttranslational modifications and regulation of the stages of the transcription cycle, DNA methylation can play a role in control of IFNβ transcription, as recently described by Gao et al (2021). 5-mC is associated with repression of regulatory DNA, X-chromosome inactivation, endogenous retro-element repression, and when located within the transcription unit, splicing (Morales-Nebreda et al, 2019).…”

“…However, it is still unclear if this regulatory methylation occurs in all IFNβ-expressing cell types, as the authors only examined human peripheral blood mononuclear cells and mouse bone marrow–derived macrophages. Unexpectedly, the single nucleotide 5-mC described by Gao et al (2021) is located 124 bp downstream of the PRD I IRF-binding site itself, within the +1 nucleosome, just 21 bp from the transcription start site ( Fig. 1 ).…”

“…Recently, Gao et al (2021) compared the induction of IFNβ during infection with influenza A virus strains, H5N1 and H1N1, and found a substantially dampened type I IFN expression in the highly pathogenic H5N1. Avian H5N1 infections usually occur through a zoonotic route, are characterized by a remarkably high fatality rate (42–82%), and remain a public health concern, especially if a related strain with increased transmissibility became prevalent.…”