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

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.

SUBMITTER: Kuppers DA 

PROVIDER: S-EPMC6787028 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature