Long-lasting immunity depends on the generation of protective antibodies through the germinal center (GC) reaction. N6-methyladenosine (m6A) modification of mRNAs by METTL3 activity modulates transcript lifetime primarily through the function of m6A readers; however, the physiological role of this molecular machinery in the GC remains unknown. Here, we show that m6A modifications by METTL3 are required for GC maintenance through the differential functions of m6A readers. Mettl3-deficient GC B cells exhibited reduced cell-cycle progression and decreased expression of proliferation- and oxidative phosphorylation–related genes. The m6A binder, IGF2BP3, was required for stabilization of Myc mRNA and expression of its target genes, whereas the m6A 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 m6A through distinct mRNA binders.
The germinal center reaction depends on RNA methylation and divergent functions of specific methyl readers
Disclosures: The authors declare no competing interests exist.
- Award Id(s): 101001613
- Award Id(s): 1090/18
- Views Icon Views
- Share Icon Share
- Search Site
Amalie C. Grenov, Lihee Moss, Sarit Edelheit, Ross Cordiner, Dominik Schmiedel, Adi Biram, Jacob H. Hanna, Torben Heick Jensen, Schraga Schwartz, Ziv Shulman; The germinal center reaction depends on RNA methylation and divergent functions of specific methyl readers. J Exp Med 4 October 2021; 218 (10): e20210360. doi: https://doi.org/10.1084/jem.20210360
Download citation file: