Epigenetic Regulation Of T Cell By The Methyltransferase Ezh2 And The Underlying Mechanisms

The immune response is a highly sophisticated and complex regulatory process.It can maintain the homeostasis and defense the disease development.T cells,whose function is regulated by the whole gene transcription level,play a pivotal role in the immune response.Post-transcriptional modification is the mainly regulatory pattern of gene transcription.Histone methyltransferease EZH2 catalyzes the three methylation of H3K27 to inhibit the expression of the target genes,thus involved in various cellular activities such as cell differentiation,cell cycle,metabolism and apoptosis.Therefore,to discover and explore the new features of EZH2 is vital for the understanding of T cell physiological activity and pathological mechanisms of T cell related diseases.EZH2-interacting proteins play decisive roles in the function of EZH2.Our study found a new EZH2-interacting protein-Ku80,a DNA repair protein.EZH2 didn't methylate Ku80 when T cells were in the normal state.Whereas DNA-PK complex assembled by Ku80 phosphorylated EZH2,changed the expression level of H3K27me3,and promoted the T cell genome stability by promoting the DNA repair and inhibiting cell apoptosis.EZH2 may play different functions to the same cell under several conditions.Hence we further studied the epigenetic regulation of T cells by EZH2 and the underlying mechanism in diseases especially inflammation.Fulminant hepatic failure(FHF)is a clinical syndrome characterized by sudden and severe impairment of liver function.We used Propionibacterium acnes(P.acnes)-primed,lipopolysaccharide(LPS)-induced liver injury in mice as an animal model of human FHF.Administration of GSK126,a kind of EZH2 inhibitor,significantly ameliorated liver injury and improved the survival rates of mice subjected to P.acnes plus LPS-induced FHF.Further mechanistic studies demonstrated that EZH2 inhibited DC maturation and finally determined the function of T cells in the immune response.In summary,EZH2 has two different regulatory function and mechanisms according to the T cell states.When T cells are under the normal state,EZH2 interacts with DNA-PK to maintaining genome stability by promoting DNA repair and inhibiting cell apoptosis.In the condition of inflammation,EZH2 regulates DC maturation and function,indirectly inhibiting the function of pathological T cells,so as to alleviate disease development.Our findings expands the understanding of EZH2's new features and provides a new strategy and potential targets for the treatment of clinically autoimmune-related diseases.