The RNA m6A binding protein YTHDF2 promotes the B cell to plasma cell transition.

To identify roles of RNA binding proteins (RBPs) in the differentiation of B cells to antibody-secreting plasma cells we performed a CRISPR/Cas9 knockout screen of 1213 mouse RBPs for their ability to affect proliferation and/or survival, and the emergence of differentiated CD138+ cells in vitro. We identified RBPs that promoted the appearance of CD138+ cells including CSDE1 and STRAP, as well as RBPs that inhibited CD138+ cell appearance such as EIF3 subunits EIF3K and EIF3L. Furthermore, we identified RBPs that share the property of recruiting the CCR4-NOT complex to their target transcripts have the potential to mediate opposing outcomes on B cell differentiation. One such RBP, the m6A binding protein YTHDF2 promotes the appearance of CD138+ cells in vitro. In chimeric mouse models YTHDF2-deficient B cells formed germinal centers in a cell-autonomous manner, however plasma cells failed to accumulate.