Histone Lysine Methyltransferase Ezh1 Promotes TLR-Triggered Inflammatory Cytokine Production by Suppressing Tollip

Abstract

Histone modifications play critical roles in the regulation of gene expression; however, their roles in the regulation of the innate response remain to be fully investigated. Using transcriptome analysis of mouse immature dendritic cells (DCs) and LPS-induced mature DCs, we identified that Ezh1 was the most upregulated histone methyltransferase during DC maturation. In this study, we investigated the role of Ezh1 in regulating the innate immune response. We found that silencing of Ezh1 significantly suppressed TLR-triggered production of cytokines, including IL-6, TNF-α, and IFN-β, in DCs and macrophages. Accordingly, TLR-activated signaling pathways were impaired in Ezh1-silenced macrophages. By transcriptome analysis of Ezh1-silenced macrophages, we found that Toll-interacting protein (Tollip), one well-known negative regulator of TLR signaling, was upregulated. Silencing of Tollip rescued TLR-triggered cytokine production in Ezh1-silenced macrophages. The SET domain of Ezh1 is essential for its enhancing effect on the TLR-triggered innate immune response and downstream signaling, indicating that Ezh1 promotes a TLR-triggered innate response through its lysine methyltransferase activity. Finally, Ezh1 was found to suppress the transcription of Tollip by directly targeting the proximal promoter of tollip and maintaining the high level of trimethylation of histone H3 lysine 27 there. Therefore, Ezh1 promotes TLR-triggered inflammatory cytokine production by suppressing the TLR negative regulator Tollip, contributing to full activation of the innate immune response against invading pathogens.

Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6

“…The monocytes were cultured in RPMI 1640 (GIBCO) supplemented with 10% heat-inactivated FBS (Invitrogen), GM-CSF (25 ng ml −1 ) and IL-4 (10 ng ml −1 ). Thioglycollate-elicited murine peritoneal macrophages (peritoneal macrophages), BMDC and macrophages (BMM) (20 ng ml −1 M-CSF) were prepared as previously reported 26 . 100 ng ml −1 LPS was used for stimulation.…”

Epigenetic Regulation of Monocyte and Macrophage Function

“…The HMTs, Ezh1 and Ezh2, are involved in functioning of PRC2. Silencing of Ezh1, an H3K27 HMT, was shown to suppress TLR-triggered production of cytokines, including IL-6, TNF, and IFN-b, in mouse DCs and macrophages (79). Ezh1 was found to suppress the transcription of Tollip by targeting the proximal promoter of Tollip and maintaining the high level of trimethylation of histone H3 lysine 27 there.…”

WITHDRAWN: Could some epigenetic modifications hold the key to opposing the metabolic syndrome?

“…The relative differences in immune gene expression between neonates and adults are associated with differences in epigenetic profiles reflecting the role of epigenetics in immune development [100][101][102]. External environmental pressure such as dietary exposure can lead to subtle variations in the epigenetic regulation of immune gene expression, that can potentially lead to more profound effects on subsequent immune function, clinical phenotype and disease risk [103][104][105]. The local tissue microenvironment is an important determinant of immune development.…”