Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA; Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL 60637, USA; Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA.
Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, Chicago, IL 60637, USA; Department of Chemistry, The University of Chicago, Chicago, IL 60637, USA.
Cell Rep. 2020 Jun 30;31(13):107819. doi: 10.1016/j.celrep.2020.107819.
The RNA N-methyladenosine (mA) 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 mA 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 mA 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 mA methylation and its reader proteins in early B cell development.
RNA N6-甲基腺苷（m6A）甲基化由 METTL3-METTL14 甲基转移酶复合物进行安装。这种修饰在各种生物过程中具有关键的调节作用。在这里，我们报告说，Mettl14 的缺失极大地减少了发育中的 B 细胞中的 mRNA m6A 甲基化，并严重阻断了小鼠 B 细胞的发育。Mettl14 的缺失会损害白细胞介素 7（IL-7）诱导的原 B 细胞增殖和大前 B 细胞向小前 B 细胞的过渡，并导致对 B 细胞发育至关重要的基因表达程序的显著异常。细胞质 m6A 读码器 YTHDF2 对 IL-7 诱导的原 B 细胞增殖中一组转录本的抑制作用至关重要。相比之下，大前 B 细胞向小前 B 细胞的过渡受阻与 YTHDF1 或 YTHDF2 无关，但与未能正确上调调节此过渡的关键转录因子有关。我们的数据强调了 RNA m6A 甲基化及其读码蛋白在早期 B 细胞发育中的重要调节作用。
