earticle

영어

A diverse antibody repertoire in B cells is generated through the various processes such as V(D)J rearrangement, class switching recombination, and somatic hypermutation at the immunoglobulin(Ig) gene loci. During early B cell development, these Ig genes are initially assembled into functional transcription units by V(D)J rearrangement, a fundamental mechanism for antibody diversity. Several lymphoid-specific factors are recognized to be involved in these recombination processes which can facilitate long-distance interaction of Ig gene segments in germ-line DNA. Proteins within the nucleocytoplasmic compartment are dynamically modified by the addition of O-linked β-N-acetylglucosamine (O-GlcNAc), derived from the end-product uridine 5’-phosphate (UDP)-GlcNAc of the hexosamine biosynthetic pathway (HBP), to serine and threonine hydroxyl groups. Modifications by O-GlcNAcylation can modulate a protein function by altering stability, subcellular localization, protein–protein interaction, phosphorylation status and/or DNA binding ability. Despite the essential role of O-GlcNAcylation in regulating protein function, the linked mechanisms of O-GlcNAcylation and V(D)J recombination remain largely unknown. Here, we show that the long-range interaction in Ig gene loci spanning >3MB is defective during V(D)J recombination in B cells from bone marrow of mice administered with O-GlcNAc inhibitors. Restricted V(D)J recombination is similarly confirmed in a mouse model with nutritional deficiency induced by limiting calorie consumption to 50%. However, defected rearrangement is restored by applying the O-GlcNAc-inducible drugs even during caloric restriction. Significantly, several factors involved in V(D)J recombination such as YY1, SMC1, and SMC3, which can regulate long-range interactions by binding to various positions in the Ig gene loci, are identified as proteins directly modified by O-GlcNAcylation. In addition, DNA binding ability of these proteins is shown to be disrupted once O-GlcNAcylation is inhibited. These results unravel a previously unidentified link between O-GlcNAcylation and V(D)J rearrangement and potentially suggests a crucial role for O-GlcNAc signaling in representing nutritional state to affect antibody diversity.