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

• Published in: Nature communications Vol. 10; no. 1; pp. 1 - 17
• Main Authors: Kuppers, Daniel A., Arora, Sonali, Lim, Yiting, Lim, Andrea R., Carter, Lucas M., Corrin, Philip D., Plaisier, Christopher L., Basom, Ryan, Delrow, Jeffrey J., Wang, Shiyan, Hansen He, Housheng, Torok-Storb, Beverly, Hsieh, Andrew C., Paddison, Patrick J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.10.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/100; 13/89; 38; 38/39; 38/47; 38/91; 45; 49; 49/90; 631/136/142; 631/1647/2210/2213; 631/337/1645/2570; 631/337/574; Biosynthesis; Bone marrow; Erythrocytes; Erythropoiesis; Gene expression; Genes; Heme; Humanities and Social Sciences; Methyltransferase; multidisciplinary; N6-methyladenosine; Osteoprogenitor cells; Regulators; RNA-binding protein; rRNA; Science; Science (multidisciplinary); Specifications; Transcription; Translation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-12518-6

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 N 6 -methyladenosine (m 6 A) mRNA methyltransferase (MTase) complex, including, METTL14 , METTL3 , and WTAP . We demonstrate that m 6 A MTase activity promotes erythroid gene expression programs through selective translation of ~300 m 6 A marked mRNAs, including those coding for SETD histone methyltransferases, ribosomal components, and polyA RNA binding proteins. Remarkably, loss of m 6 A marks results in dramatic loss of H3K4me3 marks across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each m 6 A MTase subunit and a subset of their mRNAs targets are required for human erythroid specification in primary bone-marrow derived progenitors. Thus, m 6 A mRNA marks promote the translation of a network of genes required for human erythropoiesis. Erythropoiesis can be regulated by transcriptional, epigenetic, and post-transcriptional mechanisms. Here the authors report that N 6 -methyladenosine mRNA methyltransferase complex stimulates erythropoiesis by promoting translation of specific mRNAs.