Histone Methyltransferase Ezh1Promotes TLR-triggered Inflammatory Cytokine Production By Suppressing Tollip

Histone modifications have been found to play critical roles in regulating gene expression. However, the roles of histone modifications in the regulation of innate response remain to be fully investigated. By the transcriptome analysis of mouse immature dendritic cells (DCs) and LPS-induced mature DCs, we identified that Ezhl was the most up-regulated histone methyltransferase during DCs maturation. Here we investigated the role of Ezhl in regulating innate immune response. We found that silencing of Ezhl could significantly suppress TLR-triggered production of cytokines including IL-6, TNF-a and IFN-P in DCs and macrophages. Accordingly, TLR-activated signaling pathways were impaired in Ezhl-silenced macrophages. By transcriptome analysis of Ezhl-silenced macrophages, we found Tollip, one well-known negative regulator of TLR signaling, was up-regulated. Silencing of Tollip could rescue the production of TLR-triggered cytokine production in Ezhl-silenced macrophages. SET domain of Ezhl is essential for its enhancing effect on TLR-triggered innate immune response and downstream signaling, indicating Ezhl promotes TLR-triggered innate response through its lysine methyltransferase activity. Finally, Ezhl was found to suppress the transcription of Tollip via directly targeting proximal promoter of tollip and maintaining the high level of H3K27me3there. Therefore, Ezhl promotes TLR-triggered inflammatory cytokine production by suppressing the TLR negative regulator Tollip, contributing to full activation of innate immune response against invading pathogens.