The germinal center reaction depends on RNA methylation and divergent functions of specific methyl readers

Long-lasting immunity depends on the generation of protective antibodies through the germinal center (GC) reaction. N(6)-methyladenosine (m(6)A) modification of mRNAs by METTL3 activity modulates transcript lifetime primarily through the function of m(6)A readers; however, the physiological role of this molecular machinery in the GC remains unknown. Here, we show that m(6)A modifications by METTL3 are required for GC maintenance through the differential functions of m(6)A readers. Mettl3-deficient GC B cells exhibited reduced cell-cycle progression and decreased expression of proliferation- and oxidative phosphorylation–related genes. The m(6)A binder, IGF2BP3, was required for stabilization of Myc mRNA and expression of its target genes, whereas the m(6)A reader, YTHDF2, indirectly regulated the expression of the oxidative phosphorylation gene program. Our findings demonstrate how two independent gene networks that support critical GC functions are modulated by m(6)A through distinct mRNA binders.