Longitudinal analysis of influenza vaccination implicates regulation of RIG-I signaling by DNA methylation

Abstract

Background Influenza virus infection alters the promoter DNA methylation of key immune response-related genes, including type-1 interferons and proinflammatory cytokines. However, less is known about the effect of the influenza vaccine on the epigenome. We utilized a targeted DNA methylation approach to study the longitudinal effects (day 0 pre-vaccination and day 28 post-vaccination) on influenza vaccination responses in peripheral blood mononuclear cells. Results We found that baseline, pre-vaccination methylation profiles are associated with pre-existing, protective serological immunity. Additionally, we identified 481 sites that were differentially methylated between baseline and day 28 post-vaccination. These were enriched for genes involved in the regulation of the RIG-I signaling pathway, an important regulator of viral responses. Conclusions Our results suggest that DNA methylation changes to components of the RIG-I pathway are associated with vaccine effectiveness. Therefore, immunization strategies that target this pathway may improve serological responses to influenza vaccination.

The response to influenza vaccination is associated with DNA methylation-driven regulation of T cell innate antiviral pathways

“…We included the same cohort consecutively vaccinated over two years and conducted RNA sequencing (RNA-seq) for year 2020. This comprehensive approach led to the identi cation of key methylation sites associated not only with the previously identi ed RIG-I signaling pathway but also with other genes involved in innate immunity to viruses (10). Our ndings illuminate the complex interaction between DNAm and the in uenza vaccine response, accounting for various potential confounders.…”

“…147 positive coe cients of HAI signi cant CpG sites were rst mapped to the proximal genes, and gene set enrichment results showed viral response related pathways against the full probe background to avoid selection bias. Notably, genes like C1QBP and RNF125, identi ed in this process, have been previously implicated in the RIG-I signaling pathway, as observed in the longitudinal study of the UGA4 cohort (10). Type 1 interferon production is induced downstream of the RIG-I signaling pathway, and negative regulation of type 1 interferon production was signi cantly enriched for in hypermethylated CpG sites (Table 1).…”

“…After detecting the viral component, RIG-I signaling pathway is activated to drive the transcription of interferon production. The RIG-I signaling pathway was previously shown to be involved in antiviral responses and differential methylation analysis after in uenza vaccination (10,35,36). Two genes whose methylation is signi cantly associated with HAI act as negative regulators of the RIG-I signaling pathway.…”

“…By focusing on prede ned genomic regions, TBS enables researchers to achieve high-resolution, accurate measurements of methylation levels at CpG sites within speci c target regions (9). Previously, we identi ed longitudinal changes of DNAm and found these changes were signi cant in genes associated with viral response pathways, such as the regulation of RIG-1 signaling, which leads to the production of interferons (10). Complementary to our ndings, another investigation utilized mice with site-speci c genetic modi cations and tools for targeted demethylation to establish a direct link between methylation patterns and the production of type I interferons (11).…”