Epigenetic modification, including
histone modification, precisely controls target gene expression. The posttranscriptional regulation of the innate signaling-triggered production of inflammatory
cytokines and
type I interferons has been fully elucidated, whereas the roles of
histone modification alteration and epigenetic modifiers in regulating inflammatory responses need to be further explored. Di/tri-methylation modifications of
histone 3
lysine 79 (H3K79me2/3) have been shown to be associated with gene transcriptional activation. Disruptor of telomeric silencing-1-like (Dot1l) is the only known exclusive H3K79
methyltransferase and regulates the proliferation and differentiation of
tumor cells. However, the roles of Dot1l and Dot1l-mediated H3K79 methylation in innate immunity and inflammatory responses remain unclear. Here, we found that H3K79me2/3 modification levels at the
Il6 and Ifnb1 promoters, as well as H3K79me2 modification at the Tnfα promoter, were increased in macrophages activated by
Toll-like receptor (TLR)
ligands or
virus infection. The innate signals upregulated Dot1l expression in macrophages and THP1 cells. Dot1l silencing or a Dot1l inhibitor preferentially suppressed the production of
IL-6 and
interferon (IFN)-β but not of TNF-α in macrophages and THP1 cells triggered by TLR
ligands or
virus infection. Dot1l was recruited to the proximal promoter of the
Il6 and Ifnb1 but not Tnfα gene and then mediated H3K79me2/3 modification at the
Il6 and Ifnb1 promoters, consequently facilitating the transcription and expression of
Il6 and Ifnb1. Thus, Dot1l-mediated selective H3K79me2/3 modifications at the
Il6 and Ifnb1 promoters are required for the full activation of innate immune responses. This finding adds new insights into the epigenetic regulation of inflammatory responses and pathogenesis of
autoimmune diseases.