Control of Early B Cell Development by the RNA N6-Methyladenosine Methylation.

Zheng, Zhong; Zhang, Linda; Cui, Xiao-Long; Yu, Xianbin; Hsu, Phillip J; Lyu, Ruitu; Tan, Haiyan; Mandal, Malay; Zhang, Michelle; Sun, Hui-Lung; Sanchez Castillo, Arantxa; Peng, Junmin; Clark, Marcus R; He, Chuan; Huang, Haochu

The RNA N6-methyladenosine (m6A) methylation is installed by the METTL3-METTL14 methyltransferase complex. This modification has critical regulatory roles in various biological processes. Here, we report that deletion of Mettl14 dramatically reduces mRNA m6A methylation in developing B cells and severely blocks B cell development in mice. Deletion of Mettl14 impairs interleukin-7 (IL-7)-induced pro-B cell proliferation and the large-pre-B-to-small-pre-B transition and causes dramatic abnormalities in gene expression programs important for B cell development. Suppression of a group of transcripts by cytoplasmic m6A reader YTHDF2 is critical to the IL-7-induced pro-B cell proliferation. In contrast, the block in the large-pre-B-to-small-pre-B transition is independent of YTHDF1 or YTHDF2 but is associated with a failure to properly upregulate key transcription factors regulating this transition. Our data highlight the important regulatory roles of the RNA m6A methylation and its reader proteins in early B cell development.