Regulation Of Inflammatory Innate Immune Responses And Prevention Of Autoimmune Disease Pathogenesis By Histone Methyltransferase Ash11

Histone modification is a kind of epigenetic modifications with high diversity and variability. Various amino acids on histone H1, H2, H3and H4can be modified in different ways, such as acetylation,methylation, phosphorylation, ubiquitination and so on. And lysine methylation is one of the most characterized histone modifications to date. In particular, H3K4methylation plays critical developmental roles by mediating transcriptional activation of lineage-specific genes such as Hox and Tbx families. However, the roles of H3K4methylation in immunity still remain poorly understood.Toll-like receptors (TLR) are critical for pathogen recognition and host defense against infection. Innate immune cells such as macrophages sense invading microbial pathogens via TLRs to induce downstream signaling cascades, produce proinflammatory cytokines such as IL-6, and finally protect host from infection. Various negative regulators are invovled to avoid excessive activation of TLR signals and maintain immune homeostasis. The regulation network of TLR signals has been enriched, however the involvement of H3K4methylation still needs further investigation.The primary goal of the current study is to understand the roles of H3K4methylation in innate inflammatory immune responses. For this purpose, we performed a siRNA-mediated screening test by silencing the14kinds of known enzymes involved in H3K4methylation and then detected the LPS-induced IL-6production. We found Ashll, a kind of high conserved H3K4methyltransferase, negatively regulated TLR-triggered IL-6and TNF production in macrophages by suppressing NF-κB and MAPK pathways, and finally protected host from sepsis. Ashll-silenced mice were more susceptible to autoimmune disease as a result of enhanced IL-6production. Upon TLR ligands stimulation, Ashll accumulated at the Tnfaip3promoter region, increased its H3K4modification and finally enhanced A20expression. Ashll suppressed TLR-triggered innate immune responses by A20-mediated K63deubiquitination on both TRAF6and NEMO. The suppression of Ashll on TLR signals and the activation of Ashll on A20expression were both dependent on its SET domain-mediated H3K4methyltransferase activity.Our results elucidated a crucial role of Ashll in the negative regulation of TLR-triggered innate inflammatory immune response and suppression of autoimmune diseases, providing an insight into the mechanisms of epigenetic modulation of immune responses. And Ashll might be a new potential target for the diagnosis and treatment of autoimmune diseases.