TY - JOUR
T1 - The germinal center reaction depends on RNA methylation and divergent functions of specific methyl readers
AU - Grenov, Amalie C
AU - Moss, Lihee
AU - Edelheit, Sarit
AU - Cordiner, Ross
AU - Schmiedel, Dominik
AU - Biram, Adi
AU - Hanna, Jacob H
AU - Jensen, Torben Heick
AU - Schwartz, Schraga
AU - Shulman, Ziv
N1 - This work was done with critical advice from Dr. Hadas Keren-Shaul from the Genomics Sandbox unit at the Life Science Core Facility of Weizmann Institute of Science. The graphical abstract was created with BioRender.com. Z. Shulman is supported by European Research Council grant 101001613, Israel Science Foundation grant 1090/18, Azrieli Foundation, and the Morris Kahn Institute for Human Immunology. Z. Shulman is a member of the European Molecular Biology Organization Young Investigator Program. Z. Shulman is supported by grants from the Benoziyo Endowment Fund for the Advancement of Science, the Sir Charles Clore Research Prize, Comisaroff Family Trust, Irma & Jacques Ber-Lehmsdorf Foundation, Gerald O. Mann Charitable Foundation, and David M. Polen Charitable Trust. Author contributions: A.C. Grenov designed and conducted the experiments, performed data analysis, and wrote the manuscript. L. Moss conducted smFISH experiments and data analysis. S. Edelheit prepared m6A-seq pull-downs and libraries. R. Cordiner designed and advised on m6A pull-down experiments. D. Schmiedel helped in the design and execution of some of the experiments. A. Biram assisted in single-cell Ig sequencing and analysis. J.H. Hanna provided Mettl3-deficient mice. T.H. Jensen and S. Schwartz designed and supervised m6A pull-down experiments. Z. Shulman designed experiments, supervised the study, and wrote the manuscript.
PY - 2021/8/17
Y1 - 2021/8/17
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85114397987
U2 - 10.1084/jem.20210360
DO - 10.1084/jem.20210360
M3 - Article
C2 - 34402854
SN - 0022-1007
VL - 218
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 10
M1 - e20210360
ER -