N6-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis
Daniel A. Kuppers, Sonali Arora, Yiting Lim, Andrea R. Lim, Lucas M. Carter, Philip D. Corrin, Christopher L. Plaisier, Ryan Basom, Jeffrey J. Delrow, Shiyan Wang, Housheng Hansen He, Beverly Torok-Storb, Andrew C. Hsieh & Patrick J. Paddison. Nat Commun . 2019 Oct 10;10(1):4596. PMID: 31601799 PMCID: PMC6787028
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Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we utilize a functional genomic screen for genes affecting expression of the erythroid marker CD235a/ GYPA. Among validating hits are genes coding for the N6-methyladenosine (m6A) mRNA methyltransferase (MTase) complex, including, METTL14, METTL3, and WTAP. We demonstratethat m6A MTase activity promotes erythroid gene expression programs through selective translation of ~300m6A marked mRNAs, including those coding for SETD histone methyltransferases, ribosomal components, and polyA RNA binding proteins. Remarkably, loss of m6A marks results in dramatic loss of H3K4me3 marks across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m6A MTase subunit and a subset of their mRNAs targets are required for human erythroid specification in primary bone-marrow derived progenitors. Thus, m6A mRNA marks promote the translation of a network of genes required for human erythropoiesis.
This project was partially funded by Fred Hutchinson Cancer Center Pilot and Feasability NIDDK U54 Funding and utilized the Hematopoietic Cell Procurement and Processing Services Core.