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Epigenetic regulation of innate immunity needs further identification.Dnmt3a,a de novo DNA methyltransferase,is highly expressed in terminally differentiated macrophages,however,its role in innate immunity remains unknown.Objective: To investigate whether Dnmt3a plays a role in innate immunity and then further elucidate the underlying mechanism.Methods: We measured the gene expression profile in Dnmt3a-knockdown macrophages by gene-chip and screened the cytokine production in TLR-triggered macrophages.We generated Dnmt3afl/flLyz2-Cre mice with specific deletion of Dnmt3a in myeloid and challenged Dnmt3a conditional knockout mice with RNA viruses VSV.We measured the gene expression profile in Dnmt3a-knockdown macrophage by gene-chip.We analyzed the acetylation of TBK1 immunoprecipitated from whole-cell extracts of mouse peritoneal macrophages.We analyzed the DNA methylation state of the HDAC9 distal promoter by MeDIP.Results: Here we report that deficiency of Dnmt3a selectively impairs PRR(Pattern Recognition Receptor)-triggered TBK1-dependent production of IFNα/β but not proinflammatory cytokine TNFα and IL-6.Dnmt3a-deficientmice exhibit more susceptibility to virus challenge than littermate controls.Although Dnmt3a does not directly regulate IFNα/β transcription,Dnmt3a strengthens TBK1/IRF3-initiated IFNα/β production by maintaining high expression of HDAC9 through antagonizing H3K27me3 at distal promoter of HDAC9.HDAC9 directly maintains deacetylation status of TBK1 at Lys241,enhancing TBK1 kinase activity.Conclutions: Our discovery indicates that chromatin regulator can establish macrophage-specific function for rapid and strong responding and competing pathogen infection through establishing cell-specific transcriptome during lineage commitment.These findings provide new insights into the biological function of Dnmt3a in antiviral responses and new mechanism of TBK1regulation.Our data add mechanistic insights into crosstalk of epigenetic regulation and posttranslational modification in regulation of innate signaling and activation of antiviral innate immune response.