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 () and Patrick J. Paddison ()
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Daniel A. Kuppers: Fred Hutchinson Cancer Research Center
Sonali Arora: Fred Hutchinson Cancer Research Center
Yiting Lim: Fred Hutchinson Cancer Research Center
Andrea R. Lim: Fred Hutchinson Cancer Research Center
Lucas M. Carter: Fred Hutchinson Cancer Research Center
Philip D. Corrin: Fred Hutchinson Cancer Research Center
Christopher L. Plaisier: Arizona State University
Ryan Basom: Fred Hutchinson Cancer Research Center
Jeffrey J. Delrow: Fred Hutchinson Cancer Research Center
Shiyan Wang: Princess Margaret Cancer Centre/University Health Network
Housheng Hansen He: Princess Margaret Cancer Centre/University Health Network
Beverly Torok-Storb: Fred Hutchinson Cancer Research Center
Andrew C. Hsieh: Fred Hutchinson Cancer Research Center
Patrick J. Paddison: Fred Hutchinson Cancer Research Center

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract 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 demonstrate that m6A MTase activity promotes erythroid gene expression programs through selective translation of ~300 m6A 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.

Date: 2019
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DOI: 10.1038/s41467-019-12518-6

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