Control of early B cell development by mRNA N6-methyladenosine

ABSTRACT: N6-methyladenosine (m6A) is the most abundant internal modification in eukaryotic messenger RNA (mRNA). Recent conceptual and technological advances have sparked extensive research interests in the functions of m6A, which led to the discovery of its writers, erasers and readers; as well as its regulatory roles in a number of biological processes. However, the physiological roles of mRNA m6A in B cells remained unknown. Here, we report that loss of Mettl14, the core component of the m6A writer complex, severely blocked B cell development in mice. In the bone marrow, deletion of Mettl14 in B lineage cells impaired key processes of B lymphopoiesis, including the recombination of immunoglobulin heavy chain (IgH), the IL-7-induced pro-B cell proliferation, and the transition from the large cycling pre-B stage to the small pre-B stage. Associated with these broad biological effects, Mettl14 deficiency in developing B cells dramatically decreased m6A levels in over 40% transcripts of the whole transcriptome. Global gene expression analysis in Mettl14 KO B cells showed extensive abnormalities in gene expression programs important for B cell development. To further characterize the underlying molecular mechanisms, we investigated the role of two m6A reader proteins YTHDF2 and YTHDF1. Loss of Ythdf2 impaired the IgH recombination and IL-7-induced proliferation of pro-B cells but did not affect the large pre-B-to-small pre-B cell transition. In contrast, Ythdf1 deficiency did not cause any significant defects in B cell development. These data highlighted the complexity of reader proteins that may have distinct, overlapping, or synergistic roles. Altogether, our data demonstrate that mRNA m6A modification represents a novel regulatory mechanism in early B cell development.

ORGANISM(S): Mus musculus

PROVIDER: GSE112022 | GEO | 2020/06/22

REPOSITORIES: GEO