N6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis

BioRxiv : the Preprint Server for Biology
Daniel KuppersPatrick Paddison


Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we performed a functional genomic screen for genes affecting expression of the erythroid marker CD235a/GYPA. Among validating hits were genes coding for the N6-methyladenosine (m6A) mRNA methyltransferase (MTase) complex, including, METTL14, METTL3, and WTAP. We found that m6A MTase activity promotes erythroid gene expression programs and lineage specification through selective translation of >200 m6A marked mRNAs, including those coding for SETD methyltransferase, ribosome, and polyA RNA binding proteins. Remarkably, loss of m6A marks resulted in dramatic loss of H3K4me3 across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m6A MTase subunit and a subset of their mRNAs targets, including BRD7, CXXC1, PABPC1, PABPC4, STK40, and TADA2B, were required for erythroid specification. Thus, m6A mRNA marks promote the translation of a network of genes required for human erythropoiesis.

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