B cell Tet2 promotes maturation of antibody responses through active DNA demethylation and OGT-mediated histone O-glycosylation of Aicda and Prdm1 loci
Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B711
Abstract ID: 5454
Presenting Author:
Shili Li , graduate student at UT Hlth. San Antonio
Abstract:
Epigenetic modifications modulate gene expression and cell functions. We found that expression of epigenetic Ten-Eleven-Translocation (Tet)2 factor, a potent active DNA demethylator, increases in B cells that undergo SHM/CSR and plasma cell differentiation. In AicdacreTet2fl/fl mice, activated B cell Tet2 deletion impaired maturation of T-dependent and T-independent antibody responses by dampening SHM/CSR and plasma cell differentiation through downregulation of Aicda and Prdm1 (AID and Blimp-1) expression. In addition to its DNA demethylation (catalytic) activity, Tet2 would facilitate O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT)-dependent histone O-GlcNAcylation, a gene-activating epigenetic modification. Accordingly, intrinsic B cell Tet2 deletion (in Tet2-/-B cells) decreased active DNA demethylation and histone O-GlcNAcylation in Aicda and Prdm1 promoter and enhancer regions, leading to reduced CSR and plasma cell differentiation. These were partially rescued by enforced expression of Tet2 mutants defective in catalytic or OGT-binding activity, but not by a mutant lacking both activities. Further, Tet2 and OGT inhibitors synergistically reduced Aicda and Prdm1 expression, CSR and plasma cell differentiation in human and mouse B cells, while Tet2 activator vitamin C increased Aicda and Prdm1 expression, CSR and plasma differentiation. Thus, B cell-Tet2 upregulates AID and Blimp-1 through catalytic DNA demethylation and non-catalytic OGT activity.
B cell Tet2 promotes maturation of antibody responses through active DNA demethylation and OGT-mediated histone O-glycosylation of Aicda and Prdm1 loci
Category
Poster and Podium (Block Symposium)