Stage-specific requirement for Mettl3-dependent m(6)A mRNA methylation during haematopoietic stem cell differentiation

Haematopoietic stem cells (HSCs) maintain balanced self-renewal and differentiation, but how these functions are precisely regulated is not fully understood. N(6)-methyladenosine (m(6)A) mRNA methylation has emerged as an important mode of epitranscriptional gene expression regulation affecting many biological processes. We show that deleting the m(6)A methyltransferase, Mettl3, from the adult haematopoietic system led to an accumulation of HSCs in the bone marrow and marked reduction of reconstitution potential due to a blockage of HSC differentiation. Interestingly, deleting Mettl3 from myeloid cells using Lysm-cre did not impact myeloid cell number or function. m(6)A sequencing revealed 2,073 genes with significant m(6)A modification in HSCs. Myc was identified as a direct target of m(6)A in HSCs. Mettl3-deficient HSCs failed to up-regulate MYC expression upon stimulation to differentiate and enforced expression of Myc rescued differentiation defects of Mettl3-deficient HSCs. Our results revealed a key role of m(6)A in governing HSC differentiation.