Methyltransferase Dot1l preferentially promotes innate IL-6 and IFN-? production by mediating H3K79me2/3 methylation in macrophages.

ABSTRACT: 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 Tnf? 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)-? but not of TNF-? 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 Tnf? 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.

SUBMITTER: Chen X 

PROVIDER: S-EPMC6952432 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature